MANUFACTURE, COMPOSITIONS AND USES OF COAGULATION FACTOR VIIa MODULATOR

ABSTRACT

Treatment of cancer and thromboembolic disorders using inhibitors of Factor VIIa are disclosed herein using a compound of Formula I:

CROSS-REFERENCE

This application claims the benefit of U.S. Provisional Application No.60/980,386, filed Oct. 16, 2007, which application is incorporatedherein by reference.

FIELD OF THE INVENTION

Described herein are compositions and methods for the treatment ofproliferative disorders, including cancer, and thromboembolic disordersby inhibiting coagulation Factor VIIa and/or the TF:Factor VIIa complex.

BACKGROUND OF THE INVENTION

The main role of factor VII (FVII) is to initiate the process ofcoagulation in conjunction with tissue factor (TF). Once bound to TF,FVII is activated to FVIIa.

In cancer, the TF-FVIIa complex is found in abundance in pancreatic,gastric, breast, lung, prostate, ovarian, and colon tumors, and triggersa host of physiologic processes that facilitate angiogenesis, tumorgrowth, and invasion Inhibitors of Factor VIIa block tumor growth andmetastasis, as has been shown in animal models.

SUMMARY OF THE INVENTION

Described herein are compositions of a compound of Formula I dissolvedin water (other pharmaceutically-acceptable organic solvents areoptional), in which the compositions have a pH between about 8.0 and9.5. The pH is optionally obtained by addition of a base and/or abuffer. Additional optional components in the composition areanti-crystallizing agents. Such compositions are in the form of anon-viscous aqueous solution within 15° C. of ambient (or room)temperature, including within 10° C. of room temperature, and includingwithin 5° C. of room temperature. Thus, at or around room temperature,such compositions are readily administrable subcutaneously to a humanpatient, e.g., via a narrow bore needle. As such, the viscosity and pHof the composition is such that it is suitable for subcutaneousadministration to a human patient without causing irritation or otherundesired side effects. In some embodiments, the viscosity of thecomposition increases as the temperature is decreased from roomtemperature. Further, upon refrigeration (broadly described as includingany means for cooling the composition), such compositions form athickened composition, including a gel composition (i.e., viscosity atleast 1000 cps; in some embodiments, at least 2500 cps; in someembodiments, at least 5000 cps; and in some embodiments, at least 10,000cps). In such a thickened form, the composition is more stable todegradation than in the unthickened form, and the compound of Formula Iremains dissolved (i.e., does not precipitate or crystallize out ofsolution). Further, upon removing the composition from refrigeration,the composition re-forms the unthickened solution in which the compoundof Formula I remains dissolved (i.e., suitable for subcutaneousadministration through a narrow bore needle). In some embodiments,shaking or other forms of agitation is used to accelerate this phasetransition. Further, such compositions optionally form the thickenedformulation and unthickened solution reversibly as needed, by adjustingthe temperature of the composition. As such, such compositions of acompound of Formula I retain their use as subcutaneously-administeredformulations at or around room temperature while having long-termstorage and stability upon refrigeration (in the form of anon-precipitated viscous solution/gel).

Disclosed herein, in some embodiments, is a composition comprising acompound of Formula I or a salt thereof dissolved in water:

having a pH between about 8.0 and about 9.5. In some embodiments, thesolution has a viscosity less than 100 cps, a gel, or a solution havinga viscosity greater than 100 cps. In some embodiments, the compositionfurther comprises a base, a salt thereof, or combinations thereof. Insome embodiments, the base is sodium hydroxide. In some embodiments, thecomposition further comprises a buffer. In some embodiments, the bufferis alkali phosphates, or salts of organic acids, inorganic acids oramino acids. In some embodiments, the buffer is citrate, carbonate,acetate, phosphate, triethanolamine, tromethamine, and glutamate. Insome embodiments, the buffer is tromethamine. In some embodiments, thepH between about 8.0 and about 9.5. In some embodiments, the pH isbetween about 8.2 and 9.3. In some embodiments, the pH is between about8.4 and 9.1. In some embodiments, the pH is between about 8.5 and 9.0.In some embodiments, the pH is between about 8.6 and 8.9. In someembodiments, the concentration of the compound of Formula I is greaterthan about 30 mg/mL. In some embodiments, the concentration of thecompound of Formula I is greater than about 60 mg/mL. In someembodiments, the concentration of the compound of Formula I is greaterthan about 90 mg/mL. In some embodiments, the concentration of thecompound of Formula I is about 120 mg/mL. In some embodiments, thecomposition is in the form of a solution. In some embodiments, thesolution is an aqueous solution. In some embodiments, the compositionforms a In some embodiments, the solution has a viscosity less than 100cps, a gel, or a solution having a viscosity greater than 100 cps. atabout 2° C. to about 8° C. In some embodiments, the composition revertsto a non-thickened solution when warmed to a temperature in excess ofabout 3° C. to 8° C. In some embodiments, the thickened solution is moreresistant to degradation as compared to the un-thickened solution.

Disclosed herein, in some embodiments, is a composition comprising abase or salts thereof, and a compound of Formula I or salts thereofdissolved in water:

wherein the composition is in the form of a solution having a pH betweenabout 8.0 and about 9.5. In some embodiments, the solution has aviscosity less than 100 cps, a gel, or a solution having a viscositygreater than 100 cps. In some embodiments, the base is sodium hydroxide.In some embodiments, the composition further comprises a buffer. In someembodiments, the pharmaceutically acceptable buffer is alkaliphosphates, or salts of organic acids, inorganic acids or amino acids.In some embodiments, the pharmaceutically acceptable buffer is citrate,carbonate, acetate, phosphate, triethanolamine, tromethamine, andglutamate. In some embodiments, the buffer is tromethamine. In someembodiments, the pH between about 8.0 and about 9.5. In someembodiments, the pH is between about 8.2 and 9.3. In some embodiments,the pH is between about 8.4 and 9.1. In some embodiments, the pH isbetween about 8.5 and 9.0. In some embodiments, the pH is between about8.6 and 8.9. In some embodiments, the concentration of the compound ofFormula I is greater than about 30 mg/mL. In some embodiments, theconcentration of the compound of Formula I is greater than about 60mg/mL. In some embodiments, the concentration of the compound of FormulaI is greater than about 90 mg/mL. In some embodiments, the concentrationof the compound of Formula I is about 120 mg/mL. In some embodiments,the composition is in the form of a solution. In some embodiments, thesolution is an aqueous solution. In some embodiments, the compositionforms a In some embodiments, the solution has a viscosity less than 100cps, a gel, or a solution having a viscosity greater than 100 cps. atabout 2° C. to about 8° C. In some embodiments, the composition revertsto a non-thickened solution when warmed to a temperature in excess ofabout 3° C. to 8° C. In some embodiments, the thickened solution is moreresistant to degradation as compared to the un-thickened solution.

Disclosed herein, in some embodiments, is a composition comprising acompound of Formula I dissolved in water:

and a pharmaceutically acceptable buffer wherein the composition is inthe form of a solution having a pH buffer between about 8.0 and about9.5. In some embodiments, the solution has a viscosity less than 100cps, a gel, or a solution having a viscosity greater than 100 cps. Insome embodiments, the pharmaceutically acceptable buffer is alkaliphosphates, or salts of organic acids, inorganic acids or amino acids.In some embodiments, the buffer is citrate, carbonate, acetate,phosphate, triethanolamine, tromethamine, and glutamate. In someembodiments, the buffer is tromethamine. In some embodiments, thecomposition further comprises a base, a salt thereof, or combinationsthereof. In some embodiments, the base is sodium hydroxide. In someembodiments, the pH between about 8.0 and about 9.5. In someembodiments, the pH is between about 8.2 and 9.3. In some embodiments,the pH is between about 8.4 and 9.1. In some embodiments, the pH isbetween about 8.5 and 9.0. In some embodiments, the pH is between about8.6 and 8.9. In some embodiments, the concentration of the compound ofFormula I is greater than about 30 mg/mL. In some embodiments, theconcentration of the compound of Formula I is greater than about 60mg/mL. In some embodiments, the concentration of the compound of FormulaI is greater than about 90 mg/mL. In some embodiments, the concentrationof the compound of Formula I is about 120 mg/mL. In some embodiments,the composition is in the form of a solution. In some embodiments, thesolution is an aqueous solution. In some embodiments, the compositionforms a In some embodiments, the solution has a viscosity less than 100cps, a gel, or a solution having a viscosity greater than 100 cps. atabout 2° C. to about 8° C. In some embodiments, the composition revertsto a non-thickened solution when warmed to a temperature in excess ofabout 3° C. to 8° C. In some embodiments, the thickened solution is moreresistant to degradation as compared to the un-thickened solution.

Disclosed herein, in some embodiments, is a method of modulating acoagulation cascade, comprising administering to a mammal in needthereof a composition comprising a compound of Formula I dissolved inwater:

and having a pH between about 8.0 and about 9.5. In some embodiments,the solution has a viscosity less than 100 cps, a gel, or a solutionhaving a viscosity greater than 100 cps. In some embodiments, thecomposition further comprises a base, a salt thereof, or combinationsthereof. In some embodiments, the base is sodium hydroxide. In someembodiments, the composition further comprises a buffer. In someembodiments, the buffer is alkali phosphates, or salts of organic acids,inorganic acids or amino acids. In some embodiments, the buffer iscitrate, carbonate, acetate, phosphate, triethanolamine, tromethamine,and glutamate. In some embodiments, the pH between about 8.0 and about9.5. In some embodiments, the pH is between about 8.2 and 9.3. In someembodiments, the pH is between about 8.4 and 9.1. In some embodiments,the pH is between about 8.5 and 9.0. In some embodiments, the pH isbetween about 8.6 and 8.9. In some embodiments, the concentration of thecompound of Formula I is greater than about 30 mg/mL. In someembodiments, the concentration of the compound of Formula I is greaterthan about 60 mg/mL. In some embodiments, the concentration of thecompound of Formula I is greater than about 90 mg/mL. In someembodiments, the concentration of the compound of Formula I is about 120mg/mL. In some embodiments, the composition is in the form of asolution. In some embodiments, the solution is an aqueous solution. Insome embodiments, the composition forms a In some embodiments, thesolution has a viscosity less than 100 cps, a gel, or a solution havinga viscosity greater than 100 cps. at about 2° C. to about 8° C. In someembodiments, the composition reverts to a non-thickened solution whenwarmed to a temperature in excess of about 3° C. to 8° C. In someembodiments, the thickened solution is more resistant to degradation ascompared to the un-thickened solution. In some embodiments, the compoundof Formula I is administered subcutaneously. In some embodiments, thesubcutaneous administration is accomplished by means of a syringe. Insome embodiments, the gauge of the needle on the syringe is betweenabout 20 and about 30. In some embodiments, the method further comprisesadministering radiation therapy to the mammal. In some embodiments, themethod further comprises administering an additional chemotherapeuticagent to the mammal. In some embodiments, the mammal is human. In someembodiments, the mammal is not a human.

Disclosed herein, in some embodiments, is a method of treating a cancerand/or a thromboembolic disorder, comprising administering to a mammalin need thereof a composition comprising compound of Formula I dissolvedin water:

and having a pH between about 8.0 and about 9.5. In some embodiments,the solution has a viscosity less than 100 cps, a gel, or a solutionhaving a viscosity greater than 100 cps. In some embodiments, thecomposition further comprises a base, a salt thereof, or combinationsthereof. In some embodiments, the base is sodium hydroxide. In someembodiments, the composition further comprises a buffer. In someembodiments, the buffer is alkali phosphates, or salts of organic acids,inorganic acids or amino acids. In some embodiments, the buffer iscitrate, carbonate, acetate, phosphate, triethanolamine, tromethamine,and glutamate. In some embodiments, the pH between about 8.0 and about9.5. In some embodiments, the pH is between about 8.2 and 9.3. In someembodiments, the pH is between about 8.4 and 9.1. In some embodiments,the pH is between about 8.5 and 9.0. In some embodiments, the pH isbetween about 8.6 and 8.9. In some embodiments, the concentration of thecompound of Formula I is greater than about 30 mg/mL. In someembodiments, the concentration of the compound of Formula I is greaterthan about 60 mg/mL. In some embodiments, the concentration of thecompound of Formula I is greater than about 90 mg/mL. In someembodiments, the concentration of the compound of Formula I is about 120mg/mL. In some embodiments, the composition is in the form of asolution. In some embodiments, the solution is an aqueous solution. Insome embodiments, the composition forms a In some embodiments, thesolution has a viscosity less than 100 cps, a gel, or a solution havinga viscosity greater than 100 cps. at about 2° C. to about 8° C. In someembodiments, the composition reverts to a non-thickened solution whenwarmed to a temperature in excess of about 3° C. to 8° C. In someembodiments, the thickened solution is more resistant to degradation ascompared to the un-thickened solution. In some embodiments, the compoundof Formula I is administered subcutaneously. In some embodiments, thesubcutaneous administration is accomplished by means of a syringe. Insome embodiments, the gauge of the needle on the syringe is betweenabout 20 and about 30. In some embodiments, the method further comprisesadministering radiation therapy to the mammal. In some embodiments, themethod further comprises administering an additional chemotherapeuticagent to the mammal. In some embodiments, the mammal is human. In someembodiments, the mammal is not a human.

Disclosed herein, in some embodiments, is a method of modulating tumorangiogenesis, comprising administering to a mammal in need thereof acomposition comprising a compound of Formula I dissolved in water:

and having a pH between about 8.0 and about 9.5. In some embodiments,the solution has a viscosity less than 100 cps, a gel, or a solutionhaving a viscosity greater than 100 cps. In some embodiments, thecomposition is administered at a tumor site. In some embodiments, thecomposition further comprises a base, a salt thereof, or combinationsthereof. In some embodiments, the base is sodium hydroxide. In someembodiments, the composition further comprises a buffer. In someembodiments, the buffer is alkali phosphates, or salts of organic acids,inorganic acids or amino acids. In some embodiments, the buffer iscitrate, carbonate, acetate, phosphate, triethanolamine, tromethamine,and glutamate. In some embodiments, the pH between about 8.0 and about9.5. In some embodiments, the pH is between about 8.2 and 9.3. In someembodiments, the pH is between about 8.4 and 9.1. In some embodiments,the pH is between about 8.5 and 9.0. In some embodiments, the pH isbetween about 8.6 and 8.9. In some embodiments, the concentration of thecompound of Formula I is greater than about 30 mg/mL. In someembodiments, the concentration of the compound of Formula I is greaterthan about 60 mg/mL. In some embodiments, the concentration of thecompound of Formula I is greater than about 90 mg/mL. In someembodiments, the concentration of the compound of Formula I is about 120mg/mL. In some embodiments, the composition is in the form of asolution. In some embodiments, the solution is an aqueous solution. Insome embodiments, the composition forms a In some embodiments, thesolution has a viscosity less than 100 cps, a gel, or a solution havinga viscosity greater than 100 cps. at about 2° C. to about 8° C. In someembodiments, the composition reverts to a non-thickened solution whenwarmed to a temperature in excess of about 3° C. to 8° C. In someembodiments, the thickened solution is more resistant to degradation ascompared to the un-thickened solution. In some embodiments, the compoundof Formula I is administered subcutaneously. In some embodiments, thesubcutaneous administration is accomplished by means of a syringe. Insome embodiments, the gauge of the needle on the syringe is betweenabout 20 and about 30. In some embodiments, the method further comprisesadministering radiation therapy to the mammal. In some embodiments, themethod further comprises administering an additional chemotherapeuticagent to the mammal. In some embodiments, the mammal is human. In someembodiments, the mammal is not a human.

Disclosed herein, in some embodiments, is a method of modulating thecoagulation cascade, comprising administering to a mammal a modulator ofFactor VIIa wherein the ratio of C_(max), expressed as □g/ml, toAUC_((0-∞)), expressed as □g/ml, for the modulator of the Factor VIIa isless than about 1:15. In some embodiments, the modulator of Factor VIIais administered in the form of a solution. In some embodiments, thesolution is an aqueous solution. In some embodiments, the modulator ofFactor VIIa is administered subcutaneously. In some embodiments, themodulator of Factor VIIa has a molecular weight less than 1000 amu. Insome embodiments, the modulator of Factor VIIa has the structure ofFormula I:

Disclosed herein, in some embodiments, is a method of formulating acomposition comprising a compound of Formula I, comprising mixing anaqueous solution of a compound of

Formula I:

with a buffer and one or more pH adjusting agents and adjusting the pHof the composition until the pH of the composition is between about 8.0and 9.5. In some embodiments, the buffer is alkali phosphates, or saltsof organic acids, inorganic acids or amino acids. In some embodiments,the buffer is citrate, carbonate, acetate, phosphate, triethanolamine,tromethamine, and glutamate. In some embodiments, the buffer istromethamine. In some embodiments, the pH adjusting agent is a base, anacid, or combinations thereof. In some embodiments, the base is asolution of sodium hydroxide. In some embodiments, the normality of thesodium hydroxide is about 2N. In some embodiments, the acid is asolution of hydrochloric acid. In some embodiments, the normality of thehydrochloric acid is about 1N. In some embodiments, the concentration ofthe compound of Formula I is greater than about 30 mg/mL. In someembodiments, the concentration of the compound of Formula I is greaterthan about 60 mg/mL. In some embodiments, the concentration of thecompound of Formula I is greater than about 90 mg/mL. In someembodiments, the concentration of the compound of Formula I is about 120mg/mL. In some embodiments, the pH is between about 8.2 and 9.3. In someembodiments, the pH is between about 8.4 and 9.1. In some embodiments,the pH is between about 8.5 and 9.0. In some embodiments, the pH isbetween about 8.6 and 8.9.

Disclosed herein, in some embodiments, is a device for administering acomposition comprising a compound of Formula I dissolved in water:

and having a pH between about 8.0 and about 9.5.; and wherein the devicecomprises a syringe. In some embodiments, the gauge of the needle on thesyringe is between about 20 and about 30. Disclosed herein, in someembodiments, is a composition has a pH between about 8.0 and about 9.5.Disclosed herein, in some embodiments, is a pH is between about 8.2 and9.3. Disclosed herein, in some embodiments, is a pH is between about 8.4and 9.1. Disclosed herein, in some embodiments, is a pH is between about8.5 and 9.0. Disclosed herein, in some embodiments, is a concentrationof the compound of Formula I is greater than about 30 mg/mL. Disclosedherein, in some embodiments, is a concentration of the compound ofFormula I is greater than about 60 mg/mL. Disclosed herein, in someembodiments, is a concentration of the compound of Formula I is greaterthan about 90 mg/mL. Disclosed herein, in some embodiments, is aconcentration of the compound of Formula I is about 120 mg/mL.

DESCRIPTION OF THE FIGURES

The features in the present disclosure are set forth with particularityin the appended claims. A better understanding of the features andadvantages of the present disclosure will be obtained by reference tothe following detailed description that sets forth illustrativeembodiments, in which the principles described herein are utilized, andthe accompanying drawings of which:

FIG. 1 presents an illustrative use of a compound of Formula I in lungcolonization by Bl6F10 melanoma cells in mice.

FIG. 2 presents an illustrative use of a compound of Formula I as anmodulator of Lewis lung carcinoma tumor growth in C57BL mice.

FIG. 3 presents an illustrative use of a compound of Formula I as anmodulator of Lewis lung carcinoma tumor growth in C57BL mice.

FIG. 4 presents an illustrative use of a compound of Formula I and itsFVIIa-induced IL-8 response in MDA-MB-231 human breast cancer cells.

FIG. 5 presents an illustrative example of subcutaneous bioavailabilityof a compound of Formula I in Cynomolgus monkeys.

FIG. 6 presents an illustrative graph of the mean plasma concentrationof depot and gel compositions in rabbits.

FIG. 7 presents an illustrative study of plasma concentrations of acompound of Formula I and Prothrombin time changes in C57BL/6 mice.

FIG. 8 presents an illustrative IHC data for Tissue FactorOverexpression in Tumors.

FIG. 9 presents an illustrative example of Factor VIIa as a complex withexpressed TF detected in primary pancreatic carcinoma.

FIG. 10 presents an illustrative model of Tissue Factor-FVIIa mediatedcell signaling.

FIG. 11 presents an illustrative graph of pharmacodynamic dose-responseachieved in humans.

DETAILED DESCRIPTION OF THE INVENTION Certain Definitions

In certain instances, Factor VII (hereinafter, “Factor VII”) is azymogen (i.e., an inactive enzyme precursor). In certain instances, FVIIis converted into an active enzyme (e.g. Factor VIIa).

In certain instances, plasma coagulation factor VIIa (hereinafter,“FVIIa”) is a 50 kilodalton (kDa) plasma serine protease thatparticipates in the regulation of in vivo hemostasis. In certaininstances, FVIIa is generated from FVII by the proteolysis of one ormore peptide bonds.

In certain instances, Tissue Factor (also called, thromboplastin, factorIII or CD 142; hereinafter, “TF”) is a protein that participates in thecoagulation cascade. In certain instances, TF is a receptor. In certaininstances, TF comprises three domains. In certain instances, TFcomprises (a) a domain that binds factor VIIa (i.e., the extracellulardomain); (b) a domain which crosses the hydrophobic membrane (i.e., thetransmembrane domain); and (c) a domain of 21 amino acids length insidethe cell which is involved in the signaling function of TF (i.e., thecytoplasmic domain). In certain instances, TF forms a complex withFVIIa.

The term “acceptable” with respect to a composition, composition oringredient, as used herein, means having no persistent detrimentaleffect on the general health of the individual being treated. By“pharmaceutically acceptable,” as used herein, refers to a material,such as a carrier or diluent, which does not abrogate the biologicalactivity or properties of the compound, and is relatively nontoxic,i.e., the material is administered to an individual without causingundesirable biological effects or interacting in a deleterious mannerwith any of the components of the composition in which it is contained.

As used herein, amelioration of the symptoms of a particular disease,disorder or condition by administration of a particular compound orpharmaceutical composition refers to any lessening of severity, delay inonset, slowing of progression, or shortening of duration, whetherpermanent or temporary, lasting or transient that can be attributed toor associated with administration of the compound or composition.

“Antioxidants” include, for example, butylated hydroxytoluene (BHT),sodium ascorbate, ascorbic acid, sodium metabisulfite and tocopherol. Incertain embodiments, antioxidants enhance chemical stability whererequired.

“Bioavailability” refers to the percentage of the administered dose ofcompounds disclosed herein that becomes available in the generalcirculation of the animal or human being studied. The total exposure(AUC_((0-∞))) of a drug when administered intravenously is usuallydefined as 100% bioavailable (F %). “Oral bioavailability” refers to theextent to which compounds disclosed herein are absorbed into the generalcirculation when the pharmaceutical composition is taken orally ascompared to intravenous injection.

“Blood plasma concentration” refers to the concentration of compoundsprovided herein in the plasma component of blood of a individual. It isunderstood that the plasma concentration of compounds provided hereinmay vary significantly between individuals, due to variability withrespect to metabolism and/or possible interactions with othertherapeutic agents. In accordance with one embodiment disclosed herein,the blood plasma concentration of the compounds provided herein variesfrom individual to individual. Likewise, values such as maximum plasmaconcentration (C_(max)) or time to reach maximum plasma concentration(T_(max)), or total area under the plasma concentration time curve(AUC_((0-∞))) may vary from individual to individual. Due to thisvariability, in some embodiments, the amount necessary to constitute “atherapeutically effective amount” of a compound provided herein variesfrom individual to individual.

“Carrier materials” include any commonly used excipients inpharmaceutics and should be selected on the basis of compatibility withcompounds disclosed herein and the release profile properties of thedesired dosage form. Carrier materials include, e.g., binders,suspending agents, disintegration agents, filling agents, surfactants,solubilizers, stabilizers, lubricants, wetting agents, diluents, and thelike. “Pharmaceutically compatible carrier materials” include, but arenot limited to, acacia, gelatin, colloidal silicon dioxide, calciumglycerophosphate, calcium lactate, maltodextrin, glycerine, magnesiumsilicate, polyvinylpyrrollidone (PVP), cholesterol, cholesterol esters,sodium caseinate, soy lecithin, taurocholic acid, phosphotidylcholine,sodium chloride, tricalcium phosphate, dipotassium phosphate, celluloseand cellulose conjugates, sugars sodium stearoyl lactylate, carrageenan,monoglyceride, diglyceride, pregelatinized starch, and the like.

The term “diluent” refers to chemical compounds that are used to dilutethe compound of interest prior to delivery.

“Dispersing agents,” and/or “viscosity modulating agents” includematerials that control the diffusion and homogeneity of a drug throughliquid media. Diffusion facilitators/dispersing agents include, e.g.,hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG,polyvinylpyrrolidone (PVP; commercially known as Plasdone®), and thecarbohydrate-based dispersing agents such as, for example, hydroxypropylcelluloses (e.g., HPC, HPC-SL, and HPC-L), hydroxypropylmethylcelluloses (e.g., HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M),carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate,hydroxypropylmethylcellulose acetate stearate (HPMCAS), noncrystallinecellulose, magnesium aluminum silicate, triethanolamine, polyvinylalcohol (PVA), vinyl pyrrolidone/vinyl acetate copolymer (S630),4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide andformaldehyde (also known as tyloxapol), poloxamers (e.g., PluronicsF68®, F88®, and F108®, which are block copolymers of ethylene oxide andpropylene oxide); and poloxamines (e.g., Tetronic 908®, also known asPoloxamine 908®, which is a tetrafunctional block copolymer derived fromsequential addition of propylene oxide and ethylene oxide toethylenediamine (BASF Corporation, Parsippany, N.J.)),polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidoneK25, or polyvinylpyrrolidone K30, polyvinylpyrrolidone/vinyl acetatecopolymer (S-630), polyethylene glycol, e.g., the polyethylene glycolhas a molecular weight of about 300 to about 6000, or about 3350 toabout 4000, or about 7000 to about 5400, sodium carboxymethylcellulose,methylcellulose, polysorbate-80, sodium alginate, gums, such as, e.g.,gum tragacanth and gum acacia, guar gum, xanthans, including xanthangum, sugars, cellulosics, such as, e.g., sodium carboxymethylcellulose,methylcellulose, sodium carboxymethylcellulose, polysorbate-80, sodiumalginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitanmonolaurate, povidone, carbomers, polyvinyl alcohol (PVA), alginates,chitosans and combinations thereof. Plasticizcers such as cellulose ortriethyl cellulose are also be used as dispersing agents. Dispersingagents useful in liposomal dispersions and self-emulsifying dispersionsare dimyristoyl phosphatidyl choline, natural phosphatidyl choline fromeggs, natural phosphatidyl glycerol from eggs, cholesterol and isopropylmyristate.

“Drug absorption” or “absorption” typically refers to the process ofmovement of drug from site of administration of a drug across a barrierinto a blood vessel or the site of action, e.g., a drug moving from thegastrointestinal tract into the portal vein or lymphatic system. Theterms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. For example, theresult is reduction and/or alleviation of the signs, symptoms, or causesof a disease, or any other desired alteration of a biological system.For example, an “effective amount” for therapeutic uses is the amount ofthe composition including a compound as disclosed herein required toprovide a clinically significant decrease in disease symptoms withoutundue adverse side effects. In another example, a “therapeuticallyeffective amount” is that amount of a compound of Formula I which issufficient to produce a statistically significant increase in theinhibition of Factor VIIa as determined by standard coagulation testssuch as prothrombin time. In one embodiment, an appropriate “effectiveamount” in any individual case is determined using techniques, such as adose escalation study. The term “therapeutically effective amount”includes, for example, a prophylactically effective amount. An“effective amount” of a compound disclosed herein is an amount effectiveto achieve a desired pharmacologic effect or therapeutic improvementwithout undue adverse side effects. It is understood that “an effectiveamount” or “a therapeutically effective amount” varies, in someembodiments, from individual to individual, due to variation inmetabolism of the compound administered, age, weight, general conditionof the individual, the condition being treated, the severity of thecondition being treated, and the judgment of the prescribing physician.

The terms “enhance” or “enhancing” means to increase or prolong eitherin potency or duration a desired effect. Thus, in regard to enhancingthe effect of therapeutic agents, the term “enhancing” refers to theability to increase or prolong, either in potency or duration, theeffect of other therapeutic agents on a system. An “enhancing-effectiveamount,” as used herein, refers to an amount adequate to enhance theeffect of another therapeutic agent in a desired system. When used in apatient, amounts effective for this use will depend on the severity andcourse of the disease, disorder or condition, previous therapy, thepatient's health status and response to the drugs, and the judgment ofthe treating physician.

The term “inhibiting” includes preventing, slowing, or reversing thegrowth, malignancy or spread of a tumor in a patient having cancer.

The terms “kit” and “article of manufacture” are used as synonyms.

A “measurable serum concentration” or “measurable plasma concentration”describes the blood serum or blood plasma concentration, typicallymeasured in mg, □g, or ng of therapeutic agent per ml, dl, or l of bloodserum, present in the bloodstream after administration. As used herein,measurable plasma concentrations are typically measured in ng/ml or□g/ml.

The term “modulate,” as used herein, means to interact with a targeteither directly or indirectly so as to alter the activity of the target,including, by way of example only, to enhance the activity of thetarget, to inhibit the activity of the target, to limit the activity ofthe target, or to extend the activity of the target.

As used herein, the term “modulator” refers to a compound that alters anactivity of a molecule. For example, a modulator causes an increase ordecrease in the magnitude of a certain activity of a molecule comparedto the magnitude of the activity in the absence of the modulator. Incertain embodiments, a modulator is an modulator, which decreases themagnitude of one or more activities of a molecule. In certainembodiments, an modulator completely prevents one or more activities ofa molecule. In certain embodiments, a modulator is an activator, whichincreases the magnitude of at least one activity of a molecule. Incertain embodiments the presence of a modulator results in an activitythat does not occur in the absence of the modulator.

“Pharmacodynamics” refers to the factors which determine the biologicresponse observed relative to the concentration of drug at a site ofaction.

“Pharmacokinetics” refers to the factors which determine the attainmentand maintenance of the appropriate concentration of drug at a site ofaction.

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like.

A “prodrug” refers to an agent that is converted into the parent drug invivo. Prodrugs are often useful because, in some situations, they areeasier to administer than the parent drug. They are, in someembodiments, bioavailable by oral administration whereas the parent isnot. The prodrug, in some embodiments, has improved solubility inpharmaceutical compositions over the parent drug. An example, withoutlimitation, of a prodrug would be a compound described herein, which isadministered as an ester (the “prodrug”) to facilitate transmittalacross a cell membrane where water solubility is detrimental to mobilitybut which then is metabolically hydrolyzed to the carboxylic acid, theactive entity, once inside the cell where water-solubility isbeneficial. A further example of a prodrug might be a short peptide(polyaminoacid) bonded to an acid group where the peptide is metabolizedto reveal the active moiety. In certain embodiments, upon in vivoadministration, a prodrug is chemically converted to the biologically,pharmaceutically or therapeutically more active form of the compound. Incertain embodiments, a prodrug is enzymatically metabolized by one ormore steps or processes to the biologically, pharmaceutically ortherapeutically active form of the compound. To produce a prodrug, apharmaceutically active compound is modified such that the activecompound will be regenerated upon in vivo administration. In oneembodiment, the prodrug is designed to alter the metabolic stability orthe transport characteristics of a drug, to mask side effects ortoxicity, to improve the flavor of a drug or to alter othercharacteristics or properties of a drug. Compounds provided herein, insome embodiments, are derivatized into suitable prodrugs. Upon in vivoadministration, prodrugs of the esters of alkylcarbamic acids providedherein, such as, for example, prodrugs of compounds of Formula (I), willbe metabolized to provide the parent ester of alkylcarbamic acidcompound, i.e. compounds of Formula (I) will be formed upon in vivometabolism of the prodrugs provided herein.

“Solubilizers” include compounds such as triacetin, triethylcitrate,ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium doccusate,vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone,N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropyl cyclodextrins, ethanol, n-butanol, isopropylalcohol, cholesterol, bile salts, polyethylene glycol 200-600,glycofurol, transcutol, propylene glycol, and dimethyl isosorbide andthe like.

“Stabilizers” include compounds such as any antioxidation agents,buffers, acids, preservatives and the like. In some embodiments, theFVIIa modulator composition comprises a stabilizer. Stabilizers includebut are not limited to agents that will do any of (1) improve thecompatibility of excipients with a container, or a delivery system,including a syringe or a glass bottle, (2) improve the stability of acompound of Formula I (e.g. prevent degradation), or (3) improvecomposition stability.

“Steady state,” as used herein, is when the amount of drug administeredis equal to the amount of drug eliminated within one dosing intervalresulting in a plateau or constant plasma drug exposure.

As used herein, the term “individual” is used to mean a mammal,including a human mammal and a non-human mammal. The terms patient,subject and individual are used interchangeably.

“Surfactants” include compounds such as sodium lauryl sulfate, sodiumdocusate, Tween 60 or 80, triacetin, vitamin E TPGS, sorbitanmonooleate, polyoxyethylene sorbitan monooleate, polysorbates,polaxomers, bile salts, glyceryl monostearate, copolymers of ethyleneoxide and propylene oxide, e.g., Pluronic® (BASF), and the like. Someother surfactants include polyoxyethylene fatty acid glycerides andvegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; andpolyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10,octoxynol 40. In some embodiments, surfactants are included to enhancephysical stability or for other purposes.

As used herein, the term “target activity” refers to a biologicalactivity capable of being modulated by a selective modulator. Certainexemplary target activities include, but are not limited to, bindingaffinity, signal transduction, enzymatic activity, tumor growth, andamelioration of one or more symptoms associated with a disease orcondition.

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating a disease or condition symptoms,preventing additional symptoms, ameliorating or preventing theunderlying metabolic causes of symptoms, inhibiting the disease orcondition, e.g., arresting the development of the disease or condition,relieving the disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition eitherprophylactically and/or therapeutically.

Other objects, features, and advantages of the methods and compositionsdescribed herein will become apparent from the following detaileddescription. It should be understood, however, that the detaileddescription and the specific examples, while indicating specificembodiments, are given by way of illustration only.

The Coagulation Cascade

Coagulation is one of the processes by which blood clots are formed. Incertain instances, coagulation is initiated by injury to a blood vessel.In certain instances, platelets aggregate to seal and/or reinforce thesite of injury (i.e. primary hemostasis). In certain instances,coagulation factors form fibrin strands that strengthen the aggregationof platelet (i.e. secondary hemostasis).

In certain instances, damage to a blood vessel induces the expression ofa Tissue Factor (TF) gene. In certain instances, TF forms a complex withFVII. In certain instances, the binding of TF and FVII results in theactivation of FVII. Active FVII is called FVIIa. In certain instances, aTF/FVIIa complex catalyzes the conversion of the inactive zymogen FactorX into an active protease, Factor Xa. In certain instances, a TF/FVIIacomplex catalyzes the conversion of the inactive zymogen Factor IX intoan active protease, Factor IXa. In certain instances, Factor Xa binds toFactor Va. In certain instances, a Factor IXa/Factor Va complex convertsprothrombin into its active form, thrombin. In certain instances,thrombin converts fibrinogen into fibrin.

Thrombosis is the formation of a blood clot (or thrombus) inside a bloodvessel. In certain instances, the formation of a thrombus obstructs theflow of blood through the circulatory system. In certain instances, theclinical manifestations of thrombosis (i.e. the formation of blood clotsin a blood vessel) include acute myocardial infarction (AMI or heartattack); unstable angina (UA); and deep vein thrombosis (i.e. theformation of blood clots in lower extremities; hereinafter “DVT”). Incertain instances, the formation of DVT results in the development ofpulmonary embolism (PE). In certain instances, the development of a PEis fatal.

In certain instances, thrombosis occurs systemically (i.e. microclotsform throughout the vascular system). Systemic thrombosis is known asdisseminated intravascular coagulation (DIC). In certain instances, DICresults from a viral infection (e.g. by the Ebola virus), sepsis, and/orrheumatoid arthritis. In certain instances, DIC results in a reductionin circulating coagulation factors. In certain instances, a reduction inthe number of circulating coagulation factors results in multiple organfailure, hemorrhage, and/or death.

In certain instances, the formation or embolization of blood clots in ablood vessel of the brain results in ischemic stroke. In certaininstances, triggering factors that lead to stroke are atrialfibrillation or abnormal rhythm of the atria of the heart andatherosclerosis followed by thrombosis in the main artery leading fromthe heart to the brain (carotid artery).

In certain instances, the coagulation cascade is aberrantly activated inindividuals with a cancer. In certain instances, venous thrombosis isthe first indication of malignancy in an otherwise healthy individual.In certain instances, DIC develops in patients with carcinomas of theprostate, stomach, colon, breast, ovary, lung, gall bladder and inpatients with melanoma. In certain instances, tumor cells shed membranefragments that carry TF. In certain instances, tumor cells producesoluble substances that induce TF expression on host cells (e.g.endothelium and monocytes).

In certain instances, TF is aberrantly expressed on tumor cells (e.g.lung cancer cells, colorectal cancer cells, breast cancer cells,malignant melanoma cells, gliomas cells, prostate cancer cells, gastriccancer cells, and/or ovarian cancer cells). In certain instances, theaberrant expression of TF results (partially or fully) in the initiationof angiogenic signaling. In certain instances, a tumor cell's malignancy(e.g., in colorectal and breast cancer) is proportional to the level ofTF expressed in the cell.

In certain instances, the aberrant expression of TF facilitatesmetastasis. In certain instances, metastasis involves intravasation oftumor cells from the primary tumor, survival during circulation, arrestduring microcirculation, extravasation, and tumor growth at a secondarysite. In certain instances, a TF/FVIIa is involved in multiple oncogenicprocesses required for tumor growth, angiogenesis, and tumor metastasis.

In certain instances, overexpression of TF in mouse fibrosarcoma cellsresults in the upregulation of a vascular endothelial growth factor(VEGF) gene and the downregulation of a thrombospondin gene. In certaininstances, the upregulation of a VEGF gene and the downregulation of athrombospondin gene result in increased vascularization of tumors. Incertain instances, thrombin enhances tumor cell interactions with ablood vessel wall by upregulating cell-cell adhesion molecule 1 onendothelial cells and/or the subendothelial matrix. In certaininstances, thrombin generation facilitates metastasis by alteringendothelial permeability and/or by upregulating matrix degradation.

In certain instances, siRNA-mediated knock-down of TF has little or noeffect on tumor cell proliferation and spheroid formation in vitro.

I. Compounds of Formula I

Described herein is a small molecule selective modulator of Factor VIIafor the treatment of a proliferative disorders (e.g., cancer), and/or athromboembolic disorders. The structure of the small molecule modulatorof Factor VIIa is (also referred herein as Formula I):

For example, as shown in FIG. 1, the compound of Formula I prevents lungcolonization by Bl6F10 melanoma cells in mice. In this experiment, thecompound of Formula I was administered subcutaneously 1.5 h before tumorcell inoculation, and then 4.5 h and 24 h after tumor cell inoculation.In the absence of the compound of Formula I (i.e., the vehicle alone), asubstantial number of colonies formed in the majority of the inoculatedmice. However, following the 3× dose of 50 mg/kg of the compound ofFormula I, substantially fewer colonies were formed in the mice. At thehigher dose of 3×100 mg/kg, the number of colonies further dropped. As aresult, in some embodiments, the compound of Formula I inhibit themetastasis of tumor cells.

In yet another example, as shown in FIG. 2, the compound of Formula Iinhibits Lewis lung carcinoma tumor growth in C57BL mice. In thisexample, the compound of Formula I was administered subcutaneouslystarting 4 days after tumor cell implantation in the mice (the twodifferent dosing schedules are described in FIG. 2). As can be seen inFIG. 2, there was at least a 50% reduction (p<0.01) in tumor volume,depending on the dosing schedule used. As a result, the compound ofFormula I inhibits the growth of tumor cells.

In a follow-up tumor suppression study, the compound of Formula Ireduced Lewis lung carcinoma tumor growth in C57BL mice by approximately50% when given twice daily at subcutaneous doses 22.5, 45, and 90 mg/kg(FIG. 3).

In another example, as shown in FIG. 4, MDA-MB-231 human breast cancercells were incubated in the presence of FVIIa in vitro. Secretion of thechemokine IL-8 increased to over 3-fold of baseline. The addition of a 1μM concentration of the compound of Formula I to the medium, completelyabrogated the FVIIa-induced IL-8 response.

In yet another example, as shown in FIG. 5, a study was performed incynomolgus monkeys with the compound of Formula I. Intravenous andsubcutaneous administration was performed to determine its subcutaneousbioavailability. The subcutaneous bioavailability of the test compoundfollowing a single 10.7 mg/kg dose was estimated to be 138±33%. Therelative standard deviation for systemic exposure (AUC) followingsubcutaneous dosing was 20.9% (n=3).

One of the aspects described herein is the use of a small moleculemodulator of Factor VIIa, in particular the compound of Formula I, forthe treatment of cancer. In such an aspect, a human patient havingcancer is administered a pharmaceutically acceptable compositioncontaining the compound of Formula I. Relevant primary cancers include:adrenal cortical cancer, anal cancer, bile duct cancer, bladder cancer,bone cancer, adult CNS brain tumors (including gliomas, astrocytoma,glioblastoma, oligodendroglioma, and meningioglioma), brain metastases,breast cancer, cervical cancer, childhood Non-Hodgkin's lymphoma, colonand rectum cancer, endometrial cancer, esophagus cancer, Ewing's familyof tumors, eye cancer, gallbladder cancer, gastrointestinal carcinoidtumors, gastrointestinal stromal tumors, gestational trophoblasticdisease, hematological malignancies, Hodgkin's disease, Kaposi'sarcoma,kidney cancer, laryngeal and hypopharyngeal cancer, acute lymphocyticleukemia, acute myeloid leukemia, children's leukemia, chroniclymphocytic leukemia, chronic myeloid leukemia, liver cancer, lungcancer, lung carcinoid tumors, Non-Hodgkin's lymphoma, male breastcancer, malignant mesothelioma, multiple myeloma, myelodysplasticsyndrome, nasal cavity and paranasal cancer, nasopharyngeal cancer,neuroblastoma, oral cavity and oropharyngeal cancer, osteosarcoma,ovarian cancer, pancreatic cancer, parathyroid cancer, penile cancer,pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma,salivary gland cancer, sarcoma (osteosarcoma and rhabdomyosarcoma),melanoma skin cancer, nonmelanoma skin cancer, stomach cancer,testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma,vaginal cancer, vulvar cancer, and Waldenstrom's macroglobulinemia.Relevant metastatic tumors include bone metastases. brain metastases,liver metastases, lung metastases and soft tissue metastases. In oneembodiment, the cancer is selected from: lung cancer, colorectal cancer,breast cancer, malignant melanoma, ovarian cancer, and pancreaticcancer.

Treatment of cancer includes inhibiting growth of the size of a tumor,inhibiting angiogenesis associated with a tumor, and/or inhibitingmetastasis of a tumor.

In addition, in some embodiments, the compound of Formula I is used totreat a patient in which the activity of Factor VIIa contributes to thesymptomology or severity of a disease or condition. Also, in otherembodiments, the compound of Formula I is used to treat a patient inwhich the formation of the TF-FVIIa complex contributes to thesymptomology or severity of a disease or condition. The method oftreating comprises administering to the patient the compound of FormulaI, which serves as an modulator of the activity of Factor VIIa.

The compositions containing the compound(s) described herein areadministered for prophylactic and/or therapeutic treatments. Intherapeutic applications, the compositions are administered to a patientalready suffering from a disease, condition or disorder, in an amountsufficient to cure or at least partially arrest the symptoms of thedisease, disorder or condition. Amounts effective for this use willdepend on the severity and course of the disease, disorder or condition,previous therapy, the patient's health status and response to the drugs,and the judgment of the treating physician.

In some embodiments, in the case wherein the patient's condition doesnot improve, upon the doctor's discretion the administration of thecompounds are administered chronically, that is, for an extended periodof time, including throughout the duration of the patient's life inorder to ameliorate or otherwise control or limit the symptoms of thepatient's disease or condition.

In other embodiments, in the case wherein the patient's status doesimprove, upon the doctor's discretion the administration of thecompounds are given continuously. In further embodiments the dose ofdrug being administered is temporarily reduced or temporarily suspendedfor a certain length of time (i.e., a “drug holiday”). The length of thedrug holiday varies between 2 days and 1 year, including by way ofexample only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days,12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days,120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days,320 days, 350 days, and 365 days. In other embodiments, the dosereduction during a drug holiday is from about 10% to about 100%,including by way of example only about 10%, about 15%, about 20%, about25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%,about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about90%, about 95%, and about 100%.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, can be reduced, as a function ofthe symptoms, to a level at which the improved disease, disorder orcondition is retained. Patients can, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

II. Pharmaceutical Compositions Comprising Compound I

Provided herein are pharmaceutical compositions that include a compounddescribed herein and a pharmaceutically acceptable diluent(s),excipient(s), or carrier(s). In some embodiments, the compoundsdescribed herein are administered as pharmaceutical compositions inwhich compounds described herein are mixed with other activeingredients, as in combination therapy. In some embodiments, thepharmaceutical compositions include other medicinal or pharmaceuticalagents, carriers, adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure, and/or buffers. In other embodiments, the pharmaceuticalcompositions also contain other therapeutically valuable substances.

Presented herein are compositions comprising a compound of Formula I, ora salt thereof.

In some embodiments, the composition has a concentration of a compoundof Formula I between about 1 and about 100 mM. In some embodiments, thecomposition has a concentration of a compound of Formula I between about10 and about 90 mM. In some embodiments, the composition has aconcentration of a compound of Formula I between about 20 and about 80mM. In some embodiments, the composition has a concentration of acompound of Formula I between about 30 and about 70 mM. In someembodiments, the composition has a concentration of a compound ofFormula I between about 40 and about 60 mM. In some embodiments, thecomposition has a concentration of a compound of Formula I between about50 and about 80 mM. In some embodiments, the composition has aconcentration of a compound of Formula I between about 1 and about 5 mM.

In some embodiments, the concentration of the compound of Formula I isgreater than about 30 mg/mL. In some embodiments, the concentration ofthe compound of Formula I is greater than about 60 mg/mL. In someembodiments, the concentration of the compound of Formula I is greaterthan about 90 mg/mL. In some embodiments, the concentration of thecompound of Formula I is about 120 mg/mL.

In some embodiments, the composition further comprises a base, a saltthereof, or combinations thereof. In some embodiments, the base issodium hydroxide.

In some embodiments, the composition further comprises a buffer. In someembodiments, the buffer is alkali phosphates, or salts of organic acids,inorganic acids or amino acids. In some embodiments, the buffer iscitrate, carbonate, acetate, phosphate, triethanolamine (also known asTEA), tromethamine (also known as TRIS), and glutamate.

In some embodiments, the buffer is tromethamine. Tromethamine has thechemical formula: 2-amino-2-hydroxymethyl-1,3-propanediol. It is amildly alkaline chemical compound that can be used to buffer acomposition to a pH range from about 7 to about 9.

In some embodiments, when one or more buffers are utilized in thecompositions of the present disclosure, they are combined, e.g., with apharmaceutically acceptable vehicle and are present in the finalcomposition, e.g., in an amount ranging from about 0.1% to about 20%,from about 0.5% to about 10%. In come embodiments, the amount of bufferis an amount such that the pH of the composition does not interfere withthe body's natural buffering system. In some embodiments, theconcentration of the buffer present in the composition is from about 5mM to about 200 mM. In some embodiments, the concentration of the bufferpresent in the composition is from about 20 mM to about a 100 mM.

In some embodiments, the pH of the composition is such that it issuitable for subcutaneous administration to a human patient withoutcausing irritation or other undesired side effects. In some embodiments,the pH between about 8.0 and about 9.5. In some embodiments, the pH isbetween about 8.2 and 9.3. In some embodiments, the pH is between about8.4 and 9.1. In some embodiments, the pH is between about 8.5 and 9.0.In some embodiments, the pH is between about 8.6 and 8.9.

In some embodiments, the pharmaceutical compositions described hereinare stable with respect to one or more of pH or compound degradationover a period of any of at least about 1 day, at least about 2 days, atleast about 3 days, at least about 4 days, at least about 5 days, atleast about 6 days, at least about 1 week, at least about 2 weeks, atleast about 3 weeks, at least about 4 weeks, at least about 5 weeks, atleast about 6 weeks, at least about 7 weeks, at least about 8 weeks, atleast about 1 month, at least about 2 months, at least about 3 months,at least about 4 months, at least about 5 months, or at least about 6months. In other embodiments, the compositions described herein arestable with respect to one or more of pH or compound degradation over aperiod of any of at least about 1 week. Also described herein arecompositions that are stable with respect to one or more of pH orcompound degradation over a period of any of at least about 1 month.

In some embodiments, the composition is in the form of an aqueoussolution. In some embodiments, the viscosity of the composition is suchthat it is suitable for subcutaneous administration to a human patient.In some embodiments, the composition is in the form of a non-viscousaqueous solution within 15° C. of ambient (i.e., room) temperature. Insome embodiments, the composition is in the form of a non-viscousaqueous solution within 10° C. of room temperature. In some embodiments,the composition is in the form of a non-viscous aqueous solution within5° C. of room temperature.

In some embodiments, the composition is a clear solution (e.g. there isno precipitate visible in the solution). In some embodiments, the colorof the composition is amber.

In some embodiments, the viscosity of the composition increases as thetemperature is decreased from room temperature. In some embodiments, theviscosity of the composition increases when the temperature of thecomposition is between about 2° C. to about 8° C. (e.g. refrigeratortemperature). In some embodiments, the composition is in the form of athickened solution (e.g., gel, a semi-solid, a paste, or a jelly). Insome embodiments, the composition is more resistant to degradation(i.e., stable) when in the thickened solution as compared to thenon-viscous aqueous solution. In some embodiments, a larger percentageof a compound of Formula I remains dissolved (i.e., does not precipitateor crystallize out of solution) in the thickened solution as compared tothe non-viscous aqueous solution. In some embodiments, the thickenedsolution enables long-term storage. In some embodiments, the thickenedsolution has increased stability as compared to the non-viscous aqueoussolution.

In some embodiments, the composition is in the form of a gel. In someembodiments, the viscosity of the composition is at least 1000 cps. Insome embodiments, the viscosity of the composition is at least 2500 cps.In some embodiments, the viscosity of the composition is at least 5000cps. In some embodiments, the viscosity of the composition is at least10,000 cps. In some embodiments, the viscosity of the compositionspresented herein is measured in any suitable manner. For example, insome embodiments, an LVDV-II+CP Cone Plate Viscometer and a Cone SpindleCPE-40 is used to calculate the viscosity of the compositions describedherein.

In some embodiments, the thickened solution is an opaque semi-solidmass. In some embodiments, the color of the thickened solution is brightyellow.

In some embodiments, increasing the temperature to greater than about 2°C. to about 8° C. results in the composition reverting to a non-viscousaqueous solution (i.e., suitable for subcutaneous administration througha narrow bore needle). In some embodiments, a compound of Formula Iremains dissolved in solution following reversion to a non-viscousaqueous solution. In some embodiments, the temperature is increased byany suitable manner (e.g. friction, shaking, agitation, the applicationof heat).

In some embodiments, the compositions described herein are readilyadministrable subcutaneously to a human patient. In some embodiments,the compositions described herein are readily administrablesubcutaneously to a human patient by a needle with a gauge between about20 (i.e., the nominal outer diameter is 0.902 mm) and about 33 (i.e.,the nominal outer diameter is 0.203 mm). In some embodiments, thecompositions described herein are readily administrable subcutaneouslyto a human patient by a needle with a gauge between about 22 (i.e., thenominal outer diameter is 0.711 mm) and about 31 (i.e., the nominalouter diameter is 0.254 mm). In some embodiments, the compositionsdescribed herein are readily administrable subcutaneously to a humanpatient by a needle with a gauge between about 24 (i.e., the nominalouter diameter is 0.559 mm) and about 29 (i.e., the nominal outerdiameter is 0.330 mm). In some embodiments, the compositions describedherein are readily administrable subcutaneously to a human patient by aneedle with a gauge between about 25 (i.e., the nominal outer diameteris 0.508 mm) and about 27 (i.e., the nominal outer diameter is 0.406mm).

Other Excipients

In some embodiments, the compositions described herein includeexcipients, other medicinal or pharmaceutical agents, carriers,adjuvants, such as preserving, stabilizing, wetting or emulsifyingagents, solution promoters, and salts for regulating the osmoticpressure. In other embodiments, the excipients, carriers, adjuvants, areuseful in forming a pharmaceutically acceptable thickened composition.In a further embodiment, the pharmaceutically acceptable thickenedcomposition is in the form of a gel composition.

In some embodiments, the compositions comprise a stabilizing agent. Insome embodiments, stabilizing agent is selected from, for example, fattyacids, fatty alcohols, alcohols, long chain fatty acid esters, longchain ethers, hydrophilic derivatives of fatty acids, polyvinylpyrrolidones, polyvinyl ethers, polyvinyl alcohols, hydrocarbons,hydrophobic polymers, moisture-absorbing polymers, and combinationsthereof. In some embodiments, amide analogues of stabilizers are alsoused. In a further embodiment, the chosen stabilizer changes thehydrophobicity of the composition (e.g., oleic acid, waxes), or improvesthe mixing of various components in the composition (e.g., ethanol),controls the moisture level in the formula (e.g., PVP or polyvinylpyrrolidone), controls the mobility of the phase (substances withmelting points higher than room temperature such as long chain fattyacids, alcohols, esters, ethers, amides etc. or mixtures thereof;waxes), and/or improves the compatibility of the formula withencapsulating materials (e.g., oleic acid or wax). In another embodimentsome of these stabilizers are used as solvents/co-solvents (e.g.,ethanol). In a further embodiment, stabilizers are present in sufficientamount to inhibit the degradation of a compound of Formula I. Examplesof such stabilizing agents, include, but are not limited to: (a) about0.5% to about 2% w/v glycerol, (b) about 0.1% to about 1% w/vmethionine, (c) about 0.1% to about 2% w/v monothioglycerol, (d) about 1mM to about 10 mM EDTA, (e) about 0.01% to about 2% w/v ascorbic acid,(f) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05%w/v. polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k)cyclodextrins, (1) pentosan polysulfate and other heparinoids, (m)divalent cations such as magnesium and zinc; or (n) combinationsthereof.

Other useful compositions include one or more antioxidants to enhancechemical stability where required. Suitable antioxidants include, by wayof example only, ascorbic acid and sodium metabisulfite. In oneembodiment, antioxidants are selected from metal chelating agents, thiolcontaining compounds and other general stabilizing agents.

Still other useful compositions include one or more surfactants toenhance physical stability or for other purposes. Suitable nonionicsurfactants include polyoxyethylene fatty acid glycerides and vegetableoils, e.g., polyoxyethylene (60) hydrogenated castor oil; andpolyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10,octoxynol 40.

In some embodiments, the composition comprises a gelling agent. Suitablegelling agents for use in preparation of the FVIIa modulator gelcomposition include, but are not limited to, celluloses, cellulosederivatives, cellulose ethers (e.g., carboxymethylcellulose,ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose,hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose),guar gum, xanthan gum, locust bean gum, alginates (e.g., alginic acid),silicates, starch, tragacanth, carboxyvinyl polymers, carrageenan,paraffin, petrolatum and any combinations or mixtures thereof. Othercurrently commercially-available glycerin-based gels, glycerin-derivedcompounds, conjugated, or crosslinked gels, matrices, hydrogels, andpolymers, as well as gelatins and their derivatives, alginates, andalginate-based gels, and even various native and synthetic hydrogel andhydrogel-derived compounds are all expected to be useful in thecomposition of the FVIIa modulator compositions. In some embodiments,gels include, but are not limited to, alginate hydrogels SAF-Gel(ConvaTec, Princeton, N.J.), Duoderm Hydroactive Gel (ConvaTec), Nu-gel(Johnson & Johnson Medical, Arlington, Tex.); Carrasyn (V) AcemannanHydrogel (Carrington Laboratories, Inc., Irving, Tex.); glycerin gelsElta Hydrogel (Swiss-American Products, Inc., Dallas, Tex.) and K-YSterile (Johnson & Johnson). In further embodiments, biodegradablebiocompatible gels also represent compounds present in FVIIa modulatorcompositions disclosed and described herein.

In some embodiments, the composition comprises a suspending agent.Useful suspending agents include for example only, compounds such aspolyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12,polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, orpolyvinylpyrrolidone K30, vinyl pyrrolidone/vinyl acetate copolymer(S630), polyethylene glycol, e.g., the polyethylene glycol can have amolecular weight of about 300 to about 6000, or about 3350 to about4000, or about 7000 to about 5400, sodium carboxymethylcellulose,methylcellulose, hydroxypropylmethylcellulose, hydroxymethylcelluloseacetate stearate, polysorbate-80, hydroxyethylcellulose, sodiumalginate, gums, such as, e.g., gum tragacanth and gum acacia, guar gum,xanthans, including xanthan gum, sugars, cellulosics, such as, e.g.,sodium carboxymethylcellulose, methylcellulose, sodiumcarboxymethylcellulose, hydroxypropylmethylcellulose,hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylatedsorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone andthe like. In some embodiments, useful aqueous suspensions also containone or more polymers as suspending agents. Useful polymers includewater-soluble polymers such as cellulosic polymers, e.g., hydroxypropylmethylcellulose, and water-insoluble polymers such as cross-linkedcarboxyl-containing polymers

In some embodiments, the composition comprises an additional surfactant(co-surfactant) and/or buffering agent. In some embodiments, thesurfactant and/or buffering agent is a) natural and synthetic lipophilicagents, e.g., phospholipids, cholesterol, and cholesterol fatty acidesters and derivatives thereof; b) nonionic surfactants, which includefor example, polyoxyethylene fatty alcohol esters, sorbitan fatty acidesters (Spans), polyoxyethylene sorbitan fatty acid esters (e.g.,polyoxyethylene (20) sorbitan monooleate (Tween 80), polyoxyethylene(20) sorbitan monostearate (Tween 60), polyoxyethylene (20) sorbitanmonolaurate (Tween 20) and other Tweens, sorbitan esters, glycerolesters, e.g., Myrj and glycerol triacetate (triacetin), polyethyleneglycols, cetyl alcohol, cetostearyl alcohol, stearyl alcohol,polysorbate 80, poloxamers, poloxamines, polyoxyethylene castor oilderivatives (e.g., Cremophor® RH40, Cremphor A25, Cremphor A20,Cremophor® EL) and other Cremophors, sulfosuccinates, alkyl sulphates(SLS); PEG glyceryl fatty acid esters such as PEG-8 glycerylcaprylate/caprate (Labrasol), PEG-4 glyceryl caprylate/caprate (LabrafacHydro WL 1219), PEG-32 glyceryl laurate (Gelucire 444/14), PEG-6glyceryl mono oleate (Labrafil M 1944 CS), PEG-6 glyceryl linoleate(Labrafil M 2125 CS); propylene glycol mono- and di-fatty acid esters,such as propylene glycol laurate, propylene glycol caprylate/caprate;Brij® 700, ascorbyl-6-palmitate, stearylamine, sodium lauryl sulfate,polyoxethyleneglycerol triiricinoleate, and any combinations or mixturesthereof; c) anionic surfactants include, but are not limited to, calciumcarboxymethylcellulose, sodium carboxymethylcellulose, sodiumsulfosuccinate, dioctyl, sodium alginate, alkyl polyoxyethylenesulfates, sodium lauryl sulfate, triethanolamine stearate, potassiumlaurate, bile salts, and any combinations or mixtures thereof; and d)cationic surfactants such as quartemary ammonium compounds, benzalkoniumchloride, cetyltrimethylammonium bromide, andlauryldimethylbenzyl-ammonium chloride.

In a some embodiments, when one or more co-surfactants are utilized inthe compositions of the present disclosure, they are combined, e.g.,with a pharmaceutically acceptable vehicle and is present in the finalcomposition, e.g., in an amount ranging from about 0.1% to about 20%,from about 0.5% to about 10%.

In some embodiments, the compositions described herein comprise adiluent. In some embodiments, the diluent is a salt dissolved inbuffered solutions (e.g. phosphate buffered saline solution), lactose,starch, mannitol, sorbitol, dextrose, microcrystalline cellulose such asAvicel®; dibasic calcium phosphate, dicalcium phosphate dihydrate;tricalcium phosphate, calcium phosphate; anhydrous lactose, spray-driedlactose; pregelatinized starch, compressible sugar, such as Di-Pac®(Amstar); mannitol, hydroxypropylmethylcellulose,hydroxypropylmethylcellulose acetate stearate, sucrose-based diluents,confectioner's sugar; monobasic calcium sulfate monohydrate, calciumsulfate dihydrate; calcium lactate trihydrate, dextrates; hydrolyzedcereal solids, amylose; powdered cellulose, calcium carbonate; glycine,kaolin; mannitol, sodium chloride; inositol, bentonite, or combinationsthereof.

In some embodiments, the compositions disclosed herein are isotonic.Isotonic compositions are provided by the addition of a tonicity agent.Suitable tonicity agents include, but are not limited to anypharmaceutically acceptable sugar, salt or any combinations or mixturesthereof, such as, but not limited to dextrose and sodium chloride. Infurther embodiments, the tonicity agents are present in an amount fromabout 100 mOsm/kg to about 500 mOsm/kg. In some embodiments, thetonicity agent is present in an amount from about 200 mOsm/kg to about400 mOsm/kg, from about 280 mOsm/kg to about 320 mOsm/kg.

Useful compositions also include one or more salts in an amount requiredto bring osmolality of the composition into an acceptable range. Suchsalts include those having sodium, potassium or ammonium cations andchloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate,thiosulfate or bisulfite anions; suitable salts include sodium chloride,potassium chloride, sodium thiosulfate, sodium bisulfite and ammoniumsulfate.

In some embodiments, the compositions disclosed herein comprisepreservatives. Suitable preservatives for use in the compositionsdescribed herein include, but are not limited to benzoic acid, boricacid, p-hydroxybenzoates, phenols, chlorinated phenolic compounds,alcohols, quarternary compounds, quaternary ammonium compounds (e.g.benzalkonium chloride, cetyltrimethylammonium bromide or cetylpyridiniumchloride), stabilized chlorine dioxide, mercurials (e.g. merfen orthiomersal), or mixtures thereof. In some embodiments, the preservativeis methyl paraben. In some embodiments, the methyl paraben is at aconcentration of about 0.05% to about 1.0%, about 0.1% to about 0.2%.

In some embodiments, the compositions disclosed herein comprise aviscosity enhancing agent. Viscosity agents such as, but not limited tobentonite, carbomer, ceratonia, cetostearyl alcohol, chitosan, colloidalsilicon dioxide, cyclomethicone, hypromellose, magnesium aluminumsilicate, maltitol, maltodextrin, medium chain triglycerides,polydextrose, polyvinyl alcohol, propylene glyceryl alginate, sodiumalginate, tragacanth and any combinations or mixtures thereof aresuitable for use in the compositions described herein. In addition,viscous contrast agents such as iodixanol (Visipaque, Amersham Health),and sucrose-based mediums like sucrose acetate isobutyrate (SAIB)(Eastman Chemical Company, Kingsport, Term.) are also contemplated to beuseful in some embodiments.

In some embodiments, the composition is formulated as a thickenedcomposition, comprising from about 100 □g to about 500 □g of a compoundof Formula I or a therapeutically equivalent dose of a compound ofFormula I, a polysorbate base, a pharmaceutically acceptable viscosityagent, and water for injection, the concentration of viscosity in thewater being sufficient to provide the gel composition with a finalviscosity from about 100 to about 50,000 cP. In certain embodiments, theviscosity of the gel is in the range from about 100 to about 10,000 cP,about 200 cP to about 1,000 cP, about 250 cP to about 350 cP, about 300to about 320 cP. In other embodiments, when an even more viscous mediumis desired, the biocompatible gel comprises at least about 65%, at leastabout 70%, at least about 75%, or even at least about 80% or so byweight of the compound of Formula I. In highly concentrated samples, thebiocompatible thickened composition comprises at least about 85%, atleast about 90% or at least about 95% or more by weight of the FVIIamodulator.

Suitable bases for use in a thickened composition comprising a compoundof Formula I include, but are not limited to, any pharmaceuticallyacceptable solvent. For example, suitable solvents include polyalkyleneglycols such as, but not limited to, polyethylene glycol (PEG) and anycombinations or mixtures thereof. In other embodiments, the base is acombination of a pharmaceutically acceptable surfactant and solvent.

In some embodiments, other bases include, sodium stearyl fumarate,diethanolamine cetyl sulfate, isostearate, polyethoxylated castor oil,benzalkonium chloride, nonoxyl 10, octoxynol 9, sodium lauryl sulfate,sorbitan esters (sorbitan monolaurate, sorbitan monooleate, sorbitanmonopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitantrioleate, sorbitan tristearate, sorbitan laurate, sorbitan oleate,sorbitan palmitate, sorbitan stearate, sorbitan dioleate, sorbitansesqui-isostearate, sorbitan sesquistearate, sorbitan tri-isostearate),lecithin pharmaceutical acceptable salts thereof and combinations ormixtures thereof.

In further embodiments, the base is polyethylene glycol. Polyethyleneglycol is available in many different grades having varying molecularweights. For example, polyethylene glycol is available as PEG 200; PEG300; PEG 400; PEG 540 (blend); PEG 600; PEG 900; PEG 1000; PEG 1450; PEG1540; PEG 2000; PEG 3000; PEG 3350; PEG 4000; PEG 4600 and PEG 8000. Forpurposes of the present disclosure, all grades of polyethylene glycolare contemplated for use in preparation of a stock of a compound ofFormula I. In some embodiments the polyethylene glycol used to prepare astock of a compound of Formula I is PEG 300.

In other embodiments, the base is a polysorbate. Polysorbates arenonionic surfactants of sorbitan esters. Polysorbates useful in thepresent disclosure include, but are not limited to polysorbate 20,polysorbate 40, polysorbate 60, polysorbate 80 (Tween 80) and anycombinations or mixtures thereof. In further embodiments, polysorbate 80is utilized as the pharmaceutically acceptable base.

In some embodiments, a water-soluble glycerin-based thickenedcompositions utilized in the preparation of pharmaceutical deliveryvehicles that comprise at least one compound of Formula I contains atleast about 0.1% of the water-soluble glycerin compound or more. In someembodiments, the percentage of a compound of Formula I is varied betweenabout 1% and about 95%, between about 5% and about 80%, between about10% and about 60% or more of the weight or volume of the totalpharmaceutical FVIIa modulator composition. In some embodiments, theamount of the gel compound(s) in each therapeutically useful compositionis prepared in such a way that a suitable dosage will be obtained in anygiven unit dose of the compound. Factors such as solubility,bioavailability, biological half-life, route of administration, productshelf life, as well as other pharmacological considerations arecontemplated herein and the preparation of such pharmaceuticalcompositions is presented herein.

In some embodiments, the composition further comprises one or more lipidcomplexes, liposomes, nanocapsules, microspheres, or other agents whichenhances or facilitates the pharmacokinetics of the FVIIa modulator. Inother embodiments, the compositions of the present disclosure areformulated and intended for use in therapy, particularly in the therapyof mammals, including humans, domesticated livestock, and animals underthe care of a veterinarian or other trained animal medicinepractitioner, that have, are suspected of having, or are at risk fordeveloping one or more diseases, disorders, or dysfunctions, includingfor example, cancerous tumors.

In some embodiments, a single gel composition is used, in which at leastone FVIIa modulator is present, while in other embodiments, apharmaceutical composition that comprises a mixture of two or moredistinct gel compositions is used, in which at least one FVIIa modulatoris present. In some embodiments, combinations of sols, gels and/orbiocompatible matrices is also employed to provide desirablecharacteristics of FVIIa modulator compositions. In certain embodiments,the gel compositions are cross-linked by one or more agents to alter orimprove the properties of the FVIIa modulator.

In one embodiment, combinations of one or more erosion facilitators withone or more diffusion facilitators are also used in the presentcompositions.

Methods of Preparing

Disclosed herein, in some embodiments, is a method of formulating acomposition comprising a compound of Formula I, comprising mixing anaqueous solution of a compound of Formula I:

with a buffer and one or more pH adjusting agents and adjusting the pHof the composition until the pH of the composition is between about 8.0and 9.5.

In some embodiments, the buffer is alkali phosphates, or salts oforganic acids, inorganic acids or amino acids. In some embodiments, thebuffer is citrate, carbonate, acetate, phosphate, triethanolamine,tromethamine, and glutamate. In some embodiments, the buffer istromethamine.

In some embodiments, the pH adjusting agent is a base, an acid, orcombinations thereof. In some embodiments, the base is a solution ofsodium hydroxide. The sodium hydroxide solution for pH titration wasprepared by dissolving the appropriate amount of sodium hydroxide, NF inSterile Water for Injection, USP to achieve a 2 N solution. In someembodiments, the acid is a solution of hydrochloric acid. Thehydrochloric acid solution for pH titration was prepared by mixinghydrochloric acid, NF with Sterile Water for Injection, USP to achieve a1 N solution.

In some embodiments, the composition is prepared by dissolving sodiumhydroxide, NF and tromethamine, USP in Sterile Water for Injection, USP.In some embodiments, a compound of Formula I is added to the sodiumhydroxide and tromethamine solution in portions to avoid clumping. Insome embodiments, the pH is adjusted after each portion of drugsubstance is added by dropwise addition of a 2 N sodium hydroxidesolution.

In some embodiments, the pH of the final composition is measured andadjusted with the sodium hydroxide or hydrochloric acid solutions tobring the pH within about 8.2 and about 9.3. In some embodiments, the pHis adjusted to between about 8.4 and 9.1. In some embodiments, the pH isadjusted to about 8.5 and 9.0. In some embodiments, the pH is adjustedto between about 8.6 and 8.9. In some embodiments, the composition isbrought to final weight with Sterile Water for Injection, USP

In some embodiments, the concentration of the compound of Formula I isgreater than about 30 mg/mL. In some embodiments, the concentration ofthe compound of Formula I is greater than about 60 mg/mL. In someembodiments, the concentration of the compound of Formula I is greaterthan about 90 mg/mL. In some embodiments, the concentration of thecompound of Formula I is about 120 mg/mL.

Routes of Administration

The compositions described herein are formulated for administration toan individual via any conventional means including, but not limited to,subcutaneous, other parenteral (e.g., intravenous, or intramuscular), ortransdermal administration routes.

In some embodiments, the compositions described herein are formulatedfor subcutaneous administration.

In some embodiments, the compositions described herein comprisephysiologically acceptable sterile aqueous or non-aqueous solutions,dispersions, suspensions or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions. In someembodiments, compositions described herein comprise water, ethanol,polyols (propyleneglycol, polyethylene-glycol, glycerol, cremophor andthe like), suitable mixtures thereof, vegetable oils (such as olive oil)and injectable organic esters such as ethyl oleate. Proper fluidity canbe maintained, for example, by the use of a coating such as lecithin, bythe maintenance of the required particle size in the case ofdispersions, and by the use of surfactants.

In some embodiments, the compositions described herein contain additivessuch as preserving, wetting, emulsifying, and dispensing agents.Prevention of the growth of microorganisms can be ensured by variousantibacterial and antifungal agents, such as parabens, chlorobutanol,phenol, sorbic acid, and the like. In further embodiments, it is also bedesirable to include isotonic agents, such as sugars, sodium chloride,and the like.

Prolonged absorption of the injectable pharmaceutical form can bebrought about by the use of agents delaying absorption, such as aluminummonostearate and gelatin. FVIIa modulator suspension compositionsdesigned for extended release via subcutaneous or intramuscularinjection avoid first pass metabolism and lower dosages of the compoundof Formula I described herein will be necessary to maintain plasmalevels of about 50 ng/ml. In such compositions, the particle size of thecompound of Formula I particles and the range of the particle sizes ofthe compound of Formula I particles are used to control the release of acompound of Formula I by controlling the rate of dissolution in fat ormuscle.

In one embodiment, for subcutaneous injections, compounds describedherein are formulated in aqueous solutions, in physiologicallycompatible buffers such as Hank's solution, Ringer's solution, orphysiological saline buffer. In some embodiments, for subcutaneousinjections, appropriate compositions include aqueous or nonaqueoussolutions, with physiologically compatible buffers or excipients.

In other embodiments the compositions are stable under the conditions ofmanufacture and storage and are preserved against the contaminatingaction of microorganisms, such as bacteria and fungi. In furtherembodiments, the carrier is a solvent or dispersion medium containing,for example, water, ethanol, polyol (e.g., glycerol, propylene glycol,and liquid polyethylene glycol, and the like), suitable mixturesthereof, and/or vegetable oils. In other embodiments proper fluidity ismaintained, for example, by the use of a coating, such as lecithin, bythe maintenance of the required particle size in the case of dispersionand by the use of surfactants. In some other embodiments, the preventionof the action of microorganisms are brought about by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In otherembodiments, the compositions comprise isotonic agents, for example,sugars or sodium chloride. In further embodiments, prolonged absorptionof the injectable compositions is brought about by the use in thecomposition of agents delaying absorption, for example, aluminummonostearate and gelatin.

In some embodiments, a sterile aqueous medium is employed. By way ofexample only, in one embodiment, a compound of Formula I is dissolved in1 ml of isotonic NaCl solution and added to 1000 ml of hypodermoclysisfluid or injected at the proposed site of infusion, (see for example,“Remington's Pharmaceutical Sciences” 15th Edition, pages 1035-1038 and1570-1580). In some embodiments, variation in dosage is dependent on thecondition of the individual being treated. In other embodiments, theperson responsible for administration will, in any event, determine theappropriate dose for the individual individual. Moreover, in otherembodiments, are compositions for human administration whereinpreparations meet sterility, pyrogenicity, and the general safety andpurity standards as required by FDA Office of Biologics standards.

In other embodiments, the compositions described herein are administeredto the desired site, e.g., via injection, infiltration, instillation,implantation, irrigation, or combinations thereof. Administration by anyof these methods includes the use of a delivery system such as by way ofexample an application device such as, but not limited to, a syringe, atube, and/or a sterile pad (e.g., gauze).

In some embodiments, parenteral administration comprises a bolusinjection or a continuous infusion. In another embodiment, compositionsfor injection are presented in unit dosage form, e.g., in ampoules or inmulti-dose containers, with an added preservative. In one embodiment,the pharmaceutical composition described herein is in a form suitablefor parenteral injection as a sterile suspensions, solutions oremulsions in oily or aqueous vehicles, and contains formulatory agentssuch as suspending, stabilizing and/or dispersing agents. In oneembodiment, the compound of Formula I is in an injectable composition.

Pharmaceutical compositions for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Additionally, in other embodiments, suspensions of the active compoundsare prepared as appropriate oily injection suspensions. Suitablelipophilic solvents or vehicles include fatty oils such as sesame oil,or synthetic fatty acid esters, such as ethyl oleate or triglycerides,or liposomes. In further embodiments, aqueous injection suspensionscontain substances which increase the viscosity of the suspension, suchas sodium carboxymethyl cellulose, sorbitol, or dextran. In yet afurther embodiment, the suspension also contains suitable stabilizers oragents which increase the solubility of the compounds to allow for thepreparation of highly concentrated solutions. In another embodiment, theactive ingredient is in powder form for constitution with a suitablevehicle, e.g., sterile pyrogen-free water, before use.

In one embodiment, administration of the compound occurs in a localrather than systemic manner, for example, via injection of the compounddirectly into a particular muscle tissue or an organ, often in a depotpreparation or sustained release composition. In some embodiments, suchlong acting compositions are administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection.Furthermore, in other embodiments, administration of a compound ofFormula I occurs in a targeted drug delivery system, for example, in aliposome coated with organ-specific antibody. In some other embodiment,the liposomes are targeted to and taken up selectively by the organ. Ina further embodiment, the drug is provided in the form of a rapidrelease composition, in the form of an extended release composition, orin the form of an intermediate release composition.

In some embodiments, transdermal compositions described herein areadministered using a variety of transdermal delivery devices. In someembodiments, the transdermal delivery device used with the FVIIamodulator compositions described herein comprise a power source, radiofrequency, or a brief electrical current to micro-electrodes in the skincreating “channels” or “pores” in the stratum corneum to facilitate thedelivery of the FVIIa modulator composition. In other embodiments, thetransdermal delivery device comprises a means for porating the stratumcorneum, e.g., micro-lancing, application of sonic energy, or hydraulicpuncturing, to facilitate the delivery of the FVIIa modulatorcomposition. The pores described by the methods herein are typicallyabout 20-50 microns in depth and to not extend into areas of innervationor vascularization.

The transdermal dosage forms described herein incorporate certainpharmaceutically acceptable excipients. In general, the transdermalcompositions described herein comprise at least three components: (1) aFVIIa modulator composition; (2) a penetration enhancer; and (3) anaqueous adjuvant. In addition, in some embodiments, transdermalcompositions include additional components such as, but not limited to,gelling agents, creams and ointment bases, and the like. In someembodiments, the transdermal composition further comprise a woven ornon-woven backing material to enhance absorption and prevent the removalof the transdermal composition from the skin. In other embodiments, thetransdermal compositions described herein maintain a saturated orsupersaturated state to promote diffusion into the skin.

Another useful composition for administration of compounds having thestructure of Formula I employs transdermal delivery devices (“patches”).In some embodiments, such transdermal patches are used to providecontinuous or discontinuous infusion of the compound of Formula I incontrolled amounts. The construction and use of transdermal patches forthe delivery of pharmaceutical agents is described herein. In furtherembodiments, such patches are constructed for continuous, pulsatile, oron demand delivery of pharmaceutical agents. Still further, transdermaldelivery of the compounds of Formula I are accomplished by means ofiontophoretic patches and the like. In yet a further embodiment,transdermal patches provide controlled delivery of the compounds. Therate of absorption is slowed by using rate-controlling membranes or bytrapping the compound within a polymer matrix or gel. Conversely, inother embodiments, absorption enhancers are used to increase absorption.In some embodiments, compositions suitable for transdermaladministration are presented as discrete patches and can be lipophilicemulsions or buffered, aqueous solutions, dissolved and/or dispersed ina polymer or an adhesive. In one embodiment, transdermal patches areplaced over different portions of the patient's body.

In some embodiments, compositions suitable for transdermaladministration of compounds having the structure of Formula I employtransdermal delivery devices and transdermal delivery patches and arelipophilic emulsions or buffered, aqueous solutions, dissolved and/ordispersed in a polymer or an adhesive. In other embodiments, suchpatches are constructed for continuous, pulsatile, or on demand deliveryof pharmaceutical agents. Still further, some embodiments comprisetransdermal delivery of the compounds of Formula I accomplished by meansof iontophoretic patches and the like. Additionally, in some otherembodiments, transdermal patches provide controlled delivery of thecompounds Formula I. In further embodiments the rate of absorption isslowed by using rate-controlling membranes or by trapping the compoundwithin a polymer matrix or gel. Conversely, in other embodiments,absorption enhancers are used to increase absorption. In someembodiments, absorption enhancers or carriers includes absorbablepharmaceutically acceptable solvents to assist passage through the skin.For example, transdermal devices in the form of a bandage comprising abacking member, a reservoir containing the compound optionally withcarriers, optionally a rate controlling barrier to deliver the compoundto the skin of the host at a controlled and predetermined rate over aprolonged period of time, and means to secure the device to the skin.

In some embodiments, the compound of Formula I is dissolved in anabsorbable, pharmacologically acceptable solvent to achieve passagethrough the external body layer. Suitable solvents include alcoholscontaining two to 10 carbon atoms, such as hexanol, cyclohexanol,benzylalcohol, 1,2-butanediol, glycerol, and amyl alcohol; hydrocarbonshaving five to 12 carbon atoms such as n-hexane, cyclohexane, and ethylbenzene; aldehydes and ketones having four to 10 carbon atoms such asheptyl aldehyde, cyclohexanone, and benzaldehyde; esters having four to10 carbon atoms such as amyl acetate and benzyl propionate; etherealoils such as oil of eucalyptus, oil of rue, cumin oil, limonene, thymol,and 1-pinene; halogenated hydrocarbons having two to eight carbon atomssuch as n-hexyl chloride, nhexyl bromide, and cyclohexyl chloride; ormixtures of any of the foregoing solvents. Also, in some embodiments,with a compound of Formula I, simple pharmacologically acceptablederivatives of the compound of Formula I, such as prodrugs, such asethers, esters, amides, acetals, etc. having the desired absorptionproperty are be prepared and used in practicing the present disclosure.Of course, the derivatives should be such as to convert to the activeform of the compound of Formula I within the body through the action ofbody enzyme assisted transformations, pH, etc.

In certain embodiments, delivery systems for pharmaceutical compoundsare employed, such as, for example, liposomes and emulsions. In certainembodiments, compositions provided herein can also include amucoadhesive polymer, selected from among, for example,carboxymethylcellulose, carbomer (acrylic acid polymer),poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylicacid/butyl acrylate copolymer, sodium alginate and dextran.

In some embodiments, the compounds described herein are administeredtopically and can be formulated into a variety of topicallyadministrable compositions, such as solutions, suspensions, lotions,gels, pastes, medicated sticks, balms, creams or ointments. In furtherembodiments, such pharmaceutical compounds contain solubilizers,stabilizers, tonicity enhancing agents, buffers and preservatives.

In some embodiments, the compounds described herein are also formulatedin rectal compositions such as enemas, rectal gels, rectal foams, rectalaerosols, suppositories, jelly suppositories, or retention enemas,containing conventional suppository bases such as cocoa butter or otherglycerides, as well as synthetic polymers such as polyvinylpyrrolidone,PEG, and the like. In suppository forms of the compositions, alow-melting wax such as, but not limited to, a mixture of fatty acidglycerides, optionally in combination with cocoa butter is first melted.

Gels are also used to administer drugs topically or into a body cavity,e.g., nasal passage). In addition to other types of topical gelcompositions, the FVIIa modulator compositions presented herein areadministered intra-operatively to a surgical site, whereby thecomposition is applied directly to a cut surface of the skin or to theexposed tissue, muscle or tumor site at the surgical site. Accordingly,in some embodiments, the compositions described herein must be suitable(e.g., sterile) for application to an open incision in order to reducethe risk of infection.

In some embodiments, the compositions and methods disclosed herein areused for treatment at a tumor site with an effective amount of acompound of Formula I in a composition. In one embodiment, the methodsinvolve intra-operative administration of an effective amount of atopical FVIIa modulator composition to a surgical site in a human oranimal for treating a tumor at a tumor site.

In some embodiments, administration of a single dose of a topical FVIIamodulator gel according to the methods presently described hereinminimizes and/or prevents systemic delivery of the FVIIa modulator forthe purposes of: a) producing a selective, highly-localized TF-FVIIacomplex inhibition in a discrete, localized area responsible for theformation of the tumor at the tumor site for the purpose of reducing oreliminating cancer arising from a discrete locus (i.e., producing cancercells), and b) minimizing potential adverse consequences of TF-FVIIacomplex formation. The inhibition effect provides relief from diseases,conditions, and disorders related to tumor growth for at least about 48to about 120 hours, from about 10 to about 21 days, from about 4 toabout 5 weeks, for at least about 6 to about 8 weeks, for at least about16 weeks to about 32 weeks, for at least about 52 weeks or more.

III. Methods of Treatment

Disclosed herein, in some embodiments, is a method of modulating acoagulation cascade, comprising administering to a mammal in needthereof a composition comprising a compound of Formula I:

In some embodiments, the composition further comprises a base, a saltthereof, or combinations thereof. In some embodiments, the base issodium hydroxide. In some embodiments, the composition further comprisesa buffer. In some embodiments, the buffer is alkali phosphates, or saltsof organic acids, inorganic acids or amino acids. In some embodiments,the buffer is citrate, carbonate, acetate, phosphate, triethanolamine,tromethamine, and glutamate. In some embodiments, the pH between about8.0 and about 9.5. In some embodiments, the pH is between about 8.2 and9.3. In some embodiments, the pH is between about 8.4 and 9.1. In someembodiments, the pH is between about 8.5 and 9.0. In some embodiments,the pH is between about 8.6 and 8.9. In some embodiments, theconcentration of the compound of Formula I is greater than about 30mg/mL. In some embodiments, the concentration of the compound of FormulaI is greater than about 60 mg/mL. In some embodiments, the concentrationof the compound of Formula I is greater than about 90 mg/mL. In someembodiments, the concentration of the compound of Formula I is about 120mg/mL. In some embodiments, the composition is in the form of asolution. In some embodiments, the solution is an aqueous solution. Insome embodiments, the composition forms a gel at about 2° C. to about 8°C. In some embodiments, the compound of Formula I is administeredsubcutaneously. In some embodiments, the subcutaneous administration isaccomplished by means of a syringe. In some embodiments, the gauge ofthe needle on the syringe is narrower than a 20 gauge needle. In someembodiments, the needle on the syringe is a 28 gauge needle. In someembodiments, the method further comprises administering radiationtherapy to the mammal. In some embodiments, the method further comprisesadministering an additional chemotherapeutic agent to the mammal. Insome embodiments, the mammal is human. In some embodiments, the mammalis not a human.

Disclosed herein, in some embodiments, is a method of modulating thecoagulation cascade, comprising administering to a mammal a modulator ofFactor VIIa wherein the ratio of C_(max), expressed as □g/ml, toAUC_((0-∞)), expressed as □g/ml, for the modulator of the Factor VIIa isless than about 1:15. In some embodiments, the modulator of Factor VIIais administered in the form of a solution. In some embodiments, thesolution is an aqueous solution. In some embodiments, the modulator ofFactor VIIa is administered subcutaneously. In some embodiments, themodulator of Factor VIIa has a molecular weight less than 1000 amu. Insome embodiments, the modulator of Factor VIIa has the structure ofFormula I:

Disclosed herein, in some embodiments, is a method of treating a cancerand/or a thromboembolic disorder, comprising administering to a mammalin need thereof a composition comprising compound of Formula I:

In some embodiments, the composition further comprises a base, a saltthereof, or combinations thereof. In some embodiments, the compositionfurther comprises a buffer. In some embodiments, the pH between about8.0 and about 9.5. In some embodiments, the concentration of thecompound of Formula I is about 120 mg/mL. In some embodiments, thecomposition is in the form of a solution. In some embodiments, thesolution is an aqueous solution. In some embodiments, the compositionforms a gel at about 2° C. to about 8° C. In some embodiments, thecompound of Formula I is administered subcutaneously. In someembodiments, the subcutaneous administration is accomplished by means ofa syringe. In some embodiments, the gauge of the needle on the syringeis narrower than a 20 gauge needle. In some embodiments, the needle onthe syringe is a 28 gauge needle. In some embodiments, the methodfurther comprises administering radiation therapy to the mammal. In someembodiments, the method further comprises administering an additionalchemotherapeutic agent to the mammal. In some embodiments, the mammal ishuman. In some embodiments, the mammal is not a human.

In some embodiments, the cancer is selected from adrenal corticalcancer, anal cancer, bile duct cancer, bladder cancer, bone cancer,adult CNS brain tumors (including gliomas, astrocytoma, glioblastoma,oligodendroglioma, and meningioglioma), brain metastases, breast cancer,cervical cancer, childhood Non-Hodgkin's lymphoma, colon and rectumcancer, endometrial cancer, esophagus cancer, Ewing's family of tumors,eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors,gastrointestinal stromal tumors, gestational trophoblastic disease,hematological malignancies, Hodgkin's disease, Kaposi'sarcoma, kidneycancer, laryngeal and hypopharyngeal cancer, acute lymphocytic leukemia,acute myeloid leukemia, children's leukemia, chronic lymphocyticleukemia, chronic myeloid leukemia, liver cancer, lung cancer, lungcarcinoid tumors, Non-Hodgkin's lymphoma, male breast cancer, malignantmesothelioma, multiple myeloma, myelodysplastic syndrome, nasal cavityand paranasal cancer, nasopharyngeal cancer, neuroblastoma, oral cavityand oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreaticcancer, parathyroid cancer, penile cancer, pituitary tumor, prostatecancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma(osteosarcoma and rhabdomyosarcoma), melanoma skin cancer, nonmelanomaskin cancer, stomach cancer, testicular cancer, thymus cancer, thyroidcancer, uterine sarcoma, vaginal cancer, vulvar cancer, andWaldenstrom's macroglobulinemia. Relevant metastatic tumors include bonemetastases. brain metastases, liver metastases, lung metastases and softtissue metastases. In another embodiment, the cancer can be selectedfrom: lung cancer, colorectal cancer, breast cancer, stomach cancer,malignant melanoma, ovarian cancer, and pancreatic cancer.

In some embodiments, the thromboembolic disorder is venous thrombosis(e.g. DVT) and pulmonary embolism, arterial thrombosis (e.g. inmyocardial infarction, unstable angina, thrombosis-based stroke andperipheral arterial thrombosis), and systemic embolism usually from theatrium during atrial fibrillation or from the left ventricle aftertransmural myocardial infarction, or caused by congestive heart failure;prophylaxis of reocclusion (i.e., thrombosis) after thrombolysis,percutaneous trans-luminal angioplasty (PTA) and coronary bypassoperations; the prevention of rethrombosis after microsurgery andvascular surgery in general, the prevention or treatment of venousthromboembolism associated with certain types of cancers such asprostate, stomach, colon, breast, ovary, lung, or malignant melanoma.

Disclosed herein, in some embodiments, is a method of modulating tumorangiogenesis, comprising administering to a mammal in need thereof acomposition comprising a compound of Formula I:

In some embodiments, the composition is administered at a tumor site. Insome embodiments, the composition further comprises a base, a saltthereof, or combinations thereof. In some embodiments, the base issodium hydroxide. In some embodiments, the composition further comprisesa buffer. In some embodiments, the buffer is alkali phosphates, or saltsof organic acids, inorganic acids or amino acids. In some embodiments,the buffer is citrate, carbonate, acetate, phosphate, triethanolamine,tromethamine, and glutamate. In some embodiments, the pH between about8.0 and about 9.5. In some embodiments, the pH is between about 8.2 and9.3. In some embodiments, the pH is between about 8.4 and 9.1. In someembodiments, the pH is between about 8.5 and 9.0. In some embodiments,the pH is between about 8.6 and 8.9. In some embodiments, theconcentration of the compound of Formula I is greater than about 30mg/mL. In some embodiments, the concentration of the compound of FormulaI is greater than about 60 mg/mL. In some embodiments, the concentrationof the compound of Formula I is greater than about 90 mg/mL. In someembodiments, the concentration of the compound of Formula I is about 120mg/mL. In some embodiments, the composition is in the form of asolution. In some embodiments, the solution is an aqueous solution. Insome embodiments, the composition forms a gel at about 2° C. to about 8°C. In some embodiments, the compound of Formula I is administeredsubcutaneously. In some embodiments, the subcutaneous administration isaccomplished by means of a syringe. In some embodiments, the gauge ofthe needle on the syringe is narrower than a 20 gauge needle. In someembodiments, the needle on the syringe is a 28 gauge needle. In someembodiments, the method further comprises administering radiationtherapy to the mammal. In some embodiments, the method further comprisesadministering an additional chemotherapeutic agent to the mammal. Insome embodiments, the mammal is human. In some embodiments, the mammalis not a human.

Further indications include the therapeutic and/or prophylactictreatment of disseminated intravascular coagulation caused by bacteria,multiple trauma, intoxication or any other mechanism; anticoagulanttreatment when blood is in contact with foreign surfaces in the bodysuch as vascular grafts, vascular stents, vascular catheters, mechanicaland biological prosthetic valves or any other medical device; andanticoagulant treatment when blood is in contact with medical devicesoutside the body such as during cardiovascular surgery using aheart-lung machine or in haemodialysis; the therapeutic and/orprophylactic treatment of idiopathic and adult respiratory distresssyndrome, pulmonary fibrosis following treatment with radiation orchemotherapy, septic shock, septicemia, inflammatory responses, whichinclude, but are not limited to, edema, acute or chronic atherosclerosissuch as coronary arterial disease and the formation of atheroscleroticplaques, cerebral arterial disease, cerebral infarction, cerebralthrombosis, cerebral embolism, peripheral arterial disease, ischaemia,angina (including unstable angina), reperfusion damage, restenosis afterpercutaneous trans-luminal angioplasty (PTA) and coronary artery bypasssurgery.

In a further embodiment, any combination of the disorders, diseasesand/or conditions listed herein are treated with the compounds providedherein.

VI. Combination Treatments

In some embodiments, the compositions disclosed herein are administeredin combination with an additional therapeutic agent. In someembodiments, the compositions and/or agents of the combination therapyare administered concurrently (e.g., simultaneously, essentiallysimultaneously or within the same treatment protocol) or sequentially,depending upon the nature of the disease, disorder, or condition, thecondition of the patient, and the actual choice of compositions and/oragents used.

In some embodiments, the additional therapeutic agent is an additionalanti-cancer agent, such as a topical agent, antipruritic agent, mustardapplication, bone marrow transplant, stem cell transplant, surgery,phototherapy, chemotherapy, photochemotherapy, radiation therapy,immunotherapy, radioimmunotherapy, or systemic therapy.

Examples of such anticancer agents for combination therapies include,e.g., topical steroids, BCNU (Carmustine), nitrogen mustards, phototherapy, topical imiquimod, EBD, MTX, doxorubicin (Doxil), gemcitibine,etoposide, pentostatin, cytokines, interferon, 5-aza-2′-deoxycytidine,all trans retinoic acid, doxorubicin, vincristine, etoposide,gemcitabine, imatinib (Gleevec),17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol,LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or PD184352 inany combination.

Other examples of anticancer agents for combination therapies includeTaxol™, also referred to as “paclitaxel”, an anti-cancer drug which actsby enhancing and stabilizing microtubule formation, and analogs ofTaxol™, such as Taxotere™. Compounds that have the basic taxane skeletonas a common structure feature, have also been shown to have the abilityto arrest cells in the G2-M phases due to stabilized microtubules, andin some embodiments are useful for treating cancer in combination withthe compounds described herein.

Other examples of anti-cancer agents for combination therapies includeAdriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin;aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin;altretamine; ambomycin; ametantrone acetate; aminoglutethimide;amsacrine; anastrozole; anthramycin; asparaginase; asperlin;azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide;bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycinsulfate; brequinar sodium; bropirimine; busulfan; cactinomycin;calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicinhydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin;cladribine; crisnatol mesylate; cyclophosphamide; cytarabine;dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin;dezaguanine; dezaguanine mesylate; diaziquone; doxorubicinhydrochloride; droloxifene; droloxifene citrate; dromostanolonepropionate; duazomycin; edatrexate; eflornithine hydrochloride;elsamitrucin; enloplatin; enpromate; epipropidine; epirubicinhydrochloride; erbulozole; esorubicin hydrochloride; estramustine;estramustine phosphate sodium; etanidazole; etoposide phosphate;etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine;fludarabine phosphate; fluorouracil; fluorocitabine; fosquidone;fostriecin sodium; gemcitabine hydrochloride; hydroxyurea; idarubicinhydrochloride; ifosfamide; iimofosine; interleukin I1 (includingrecombinant interleukin II, or r1L2), interferon alfa-2a; interferonalfa-2b; interferon alfa-n1; interferon alfa-n3; interferon beta-1a;interferon gamma-1 b; iproplatin; irinotecan hydrochloride; lanreotideacetate; letrozole; leuprolide acetate; liarozole hydrochloride;lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol;maytansine; mechlorethamine hydrochloride; megestrol acetate;melengestrol acetate; melphalan; menogaril; mercaptopurine;methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide;mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper;mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazoie;nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin;pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan;piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium;porfiromycin; prednimustine; procarbazine hydrochloride; puromycin;puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol;safingol hydrochloride; semustine; simtrazene; sparfosate sodium;sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin;streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium;tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;tirapazamine; toremifene citrate; trestolone acetate; triciribinephosphate; trimetrexate; trimetrexate glucuronate; triptorelin;tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;verteporfin; vinblastine sulfate; vindesine; vindesine sulfate;vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate;vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate;vorozole; zeniplatin; zinostatin; zorubicin hydrochloride.

Other examples of anti-cancer agents for combination therapies include:20-epi-1, 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone;aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TKantagonists; altretamine; ambamustine; amidox; amifostine;aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;andrographolide; angiogenesis inhibitors; antagonist D; antagonist G;antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen,prostatic carcinoma; antiestrogen; antineoplaston; antisenseoligonucleotides; aphidicolin glycinate; apoptosis gene modulators;apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; argininedeaminase; asulacrine; atamestane; atrimustine; axinastatin 1;axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatinIII derivatives; balanol; batimastat; BCR/ABL antagonists;benzochlorins; benzoylstaurosporine; beta lactam derivatives;beta-alethine; betaclamycin B; betulinic acid; bFGF modulator;bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistrateneA; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine;calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2;capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRestM3; CARN 700; cartilage derived modulator; carzelesin; casein kinaseinhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins;chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine;clomifene analogues; clotrimazole; collismycin A; collismycin B;combretastatin A4; combretastatin analogue; conagenin; crambescidin 816;crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A;cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate;cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B;deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;diaziquone; didemnin B; didox; diethylnorspermine;dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine; docosanol;dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA;ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene;emitefur; epirubicin; epristeride; estramustine analogue; estrogenagonists; estrogen antagonists; etanidazole; etoposide phosphate;exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride;flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor modulator; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF modulator; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance genemodulator; multiple tumor suppressor 1-based therapy; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin;pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine;pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin;pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator modulator; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C modulator; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylerie conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP modulator; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived modulator 1; sense oligonucleotides;signal transduction inhibitors; signal transduction modulators; singlechain antigen-binding protein; sizofuran; sobuzoxane; sodiumborocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell modulator; stem-celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; totipotent stem cell factor;translation inhibitors; tretinoin; triacetyluridine; triciribine;trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinaseinhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenitalsinus-derived growth inhibitory factor; urokinase receptor antagonists;vapreotide; variolin B; vector system, erythrocyte gene therapy;velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine;vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatinstimalamer.

Yet other examples of anticancer agents for combination therapiesinclude alkylating agents, antimetabolites, natural products, orhormones, e.g., nitrogen mustards (e.g., mechloroethamine,cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g.,busulfan), nitrosoureas (e.g., carmustine, lomusitne, ete.), ortriazenes (decarbazine, etc.). Examples of antimetabolites include butare not limited to folic acid analog (e.g., methotrexate), or pyrimidineanalogs (e.g., Cytarabine), purine analogs (e.g., mercaptopurine,thioguanine, pentostatin).

Examples of natural products useful as anticancer for combinationtherapies include but are not limited to vinca alkaloids (e.g.,vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide),antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g.,L-asparaginase), or biological response modifiers (e.g., interferonalpha).

Examples of alkylating agents for combination therapies include, but arenot limited to, nitrogen mustards (e.g., mechloroethamine,cyclophosphamide, chlorambucil, meiphalan, etc.), ethylenimine andmethylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates(e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine,streptozocin, etc.), or triazenes (decarbazine, ete.). Examples ofantimetabolites include, but are not limited to folic acid analog (e.g.,methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxouridine,Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine,pentostatin.

Examples of hormones and antagonists useful as anticancer agents forcombination therapies include, but are not limited to,adrenocorticosteroids (e.g., prednisone), progestins (e.g.,hydroxyprogesterone caproate, megestrol acetate, medroxyprogesteroneacetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol),antiestrogen (e.g., tamoxifen), androgens (e.g., testosteronepropionate, fluoxymesterone), antiandrogen (e.g., flutamide),gonadotropin releasing hormone analog (e.g., leuprolide). Other examplesof anticancer agents that can be used in in combination with acomposition containing a selective HDAC8 inhibiter include platinumcoordination complexes (e.g., cisplatin, carboblatin), anthracenedione(e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methylhydrazine derivative (e.g., procarbazine), adrenocortical suppressant(e.g., mitotane, aminoglutethimide).

Examples of anti-cancer agents which act by arresting cells in the G2-Mphases due to stabilized microtubules for combination therapies includewithout limitation the following marketed drugs and drugs indevelopment: Erbulozole (also known as R-55104), Dolastatin 10 (alsoknown as DLS-10 and NSC-376128), Mivobulin isethionate (also known asCI-980), Vincristine, NSC-639829, Discodermolide (also known asNVP-XX-A-296), ABT-751 (Abbott, also known as E-7010), Altorhyrtins(such as Altorhyrtin A and Altorhyrtin C), Spongistatins (such asSpongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4,Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, andSpongistatin 9), Cemadotin hydrochloride (also known as LU-103793 andNSC-D-669356), Epothilones (such as Epothilone A, Epothilone B,Epothilone C (also known as desoxyepothilone A or dEpoA), Epothilone D(also referred to as KOS-862, dEpoB, and desoxyepothilone B), EpothiloneE, Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide,16-aza-epothilone B, 21-aminoepothilone B (also known as BMS-310705),21-hydroxyepothilone D (also known as Desoxyepothilone F and dEpoF),26-fluoroepothilone, Auristatin PE (also known as NSC-654663),Soblidotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known asLS-4577), LS-4578 (Pharmacia, also known as LS-477-P), LS-4477(Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), Vincristinesulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known asWS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy ofSciences), BSF-223651 (BASF, also known as ILX-651 and LU-223651),SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97(Armad/Kyowa Hakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko),IDN-5005 (Indena), Cryptophycin 52 (also known as LY-355703), AC-7739(Ajinomoto, also known as AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto,also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A),Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (also known asNSC-106969), T-138067 (Tularik, also known as T-67, TL-138067 andTI-138067), COBRA-1 (Parker Hughes Institute, also known as DDE-261 andWHI-261), H10 (Kansas State University), H16 (Kansas State University),Oncocidin A1 (also known as BTO-956 and DIME), DDE-313 (Parker HughesInstitute), Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute),SPA-1 (Parker Hughes Institute, also known as SPIKET-P), 3-IAABU(Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-569),Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica),A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai Schoolof Medicine, also known as MF-191), TMPN (Arizona State University),Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, lnanocine(also known as NSC-698666), 3-1AABE (Cytoskeleton/Mt. Sinai School ofMedicine), A-204197 (Abbott), T-607 (Tuiarik, also known as T-900607),RPR-115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin,Desaetyleleutherobin, lsoeleutherobin A, and Z-Eleutherobin),Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica),D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350(Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott),Diozostatin, (−)-Phenylahistin (also known as NSCL-96F037), D-68838(Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris,also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286(also known as SPA-110, trifluoroacetate salt) (Wyeth), D-82317(Zentaris), D-82318 (Zentaris), SC-12983 (NCl), Resverastatin phosphatesodium, BPR-OY-007 (National Health Research Institutes), and SSR-250411(Sanofi).

In some embodiments, the additional therapeutic agent is an additionalanticoagulant. In some embodiments, the anticoagulant is a thrombinmodulator, a factor IXa modulator, a factor Xa modulator, orcombinations thereof. In some embodiments, the thrombin modulator isInogatran®, Melagatran® or prodrugs thereof. In some embodiments, theFactor Xa modulator is described in Current Opinion in TherapeuticPatents, 1993, 1173-1179 (which is hereby incorporated by reference forsuch disclosures); 4-{4-[4-(5-chloroindol-2-ylsulfonyl)piperazine-1-carbonyl]phenyl}-pyridine-1-oxide; antistatin; a tickanticoagulant peptide (TAP); SQ-311; SQ-315; SN-292; SN-429; SN 116;RPR-208707; XU-817; SF-324; SF-303; YM 60828; FACTOREX; SF-324; DX9065A;1-(4-carbamimidoylbenzyl)-4-(6-chloronaphthalene-2-ylsulfonyl)-piperazin-2-one;M55555; DPC423 (1-(3-carbamimidoylphenyl)-2-(2′-aminolsulfonyl[1,l′-biphenyl]-4-ylaminocarbonyl)-4-bromopyrrole,3-(3,5-difluoro-6-[3-(4,5-dihydro-1-methylimidazol-2-yl)-phenoxy]-4-[2,3-dihydroxy-propoxy]-pyridin-2-yloxy)-4-hydroxybenzamidine;ZK-807834;1,4-diaza-4-(6-chloronaphthalene-2-ylsulfonyl)-6-(methoxymethyl)-7-oxa-P-(pyridin-4-yl)spiro[b]cyclo-[4-3.0]-nonane-8,4′-piperidine]-2-one;(S)-1-(4-aminoquinazolin-7-ylmethyl)-4-[2-(5-chlorothien-2-yloxy)acetyl]-3-methoxy-methylpiperazin-2-one;3-(2-[4-(2-aminosulfonyl-phenyl)benzoylphenoxy)-benzamidine; and4-(2-[4-(5-chloroindol-2-yl-sulfonyl)-2-(pyrrolidin-1-ylcarbonylmethyl)piperazin-1-yl-carbonyl]-thiazol-5-yl)pyridineN-oxide.

In some embodiments, therapeutically effective dosages vary when thecompositions are used in treatment combinations. Methods forexperimentally determining therapeutically effective dosages ofcompositions and/or agents for use in combination treatment regimens aredescribed in the literature. For example, the use of metronomic dosing,i.e., providing more frequent, lower doses in order to minimize toxicside effects, has been described extensively in the literature.Combination treatment further includes periodic treatments that startand stop at various times to assist with the clinical management of thepatient.

For combination therapies described herein, dosages of theco-administered compositions and/or agents will of course vary dependingon the type of co-drug employed, on the specific drug employed, on thedisease or condition being treated and so forth. In addition, in someembodiments, when co-administered with one or more biologically activeagents, the compound provided herein is administered eithersimultaneously with the biologically active agent(s), or sequentially.If administered sequentially, the attending physician will decide on theappropriate sequence of administering protein in combination with thebiologically active agent(s).

In any case, in other embodiments, the multiple compositions and/oragents (one of which is a compound of Formula I) is administered in anyorder or even simultaneously. If simultaneously, the multipletherapeutic agents are provided in a single, unified form, or inmultiple forms. In further embodiments, one of the therapeutic agents isgiven in multiple doses, or both are given as multiple doses. If notsimultaneous, in other embodiments, the timing between the multipledoses varies from more than zero weeks to less than four weeks. Inaddition, the combination methods, compositions and compositions are notto be limited to the use of only two agents; the use of multipletherapeutic combinations is also envisioned.

In some embodiments, the agents that make up the combination therapydisclosed herein are in a combined dosage form or in separate dosageforms intended for substantially simultaneous administration. In furtherembodiments, the agents that make up the combination therapy are alsoadministered sequentially, with either therapeutic agent beingadministered by a regimen calling for a two-step administration. In yetfurther embodiments, the two-step administration regimen calls forsequential administration of the active agents or spaced-apartadministration of the separate active agents. In one embodiment, thetime period between the multiple administration steps ranges from, a fewminutes to several hours, depending upon the properties of eachpharmaceutical agent, such as potency, solubility, bioavailability,plasma half-life and kinetic profile of the pharmaceutical agent. Infurther embodiments, circadian variation of the target moleculeconcentration also determines the optimal dose interval.

In some embodiments, the components of the combination therapies areadministered before, during or after the occurrence of a disease orcondition, and the timing of administering the composition containing acompound of Formula I is varied. Thus, for example, in some embodiments,the compositions are used as a prophylactic and are administeredcontinuously to individuals with a propensity to develop conditions ordiseases in order to prevent the occurrence of the disease or condition.In another embodiment, the compositions are administered to a individualduring or as soon as possible after the onset of the symptoms. In afurther embodiment, the administration of the composition is initiatedwithin the first 48 hours of the onset of the symptoms, within the first48 hours of the onset of the symptoms, within the first 6 hours of theonset of the symptoms, and within 3 hours of the onset of the symptoms.In yet a further embodiment, the initial administration is via any routepractical, such as, for example, an intravenous injection, a bolusinjection, infusion over 5 minutes to about 5 hours, a pill, a capsule,transdermal patch, buccal delivery, and the like, or combinationthereof. In yet other embodiments, the composition is administered assoon as is practicable after the onset of a disease or condition isdetected or suspected, and for a length of time necessary for thetreatment of the disease, such as, for example, from about 1 month toabout 3 months. In another embodiment, the length of treatment variesfor each individual, and the length is determined using the knowncriteria. For example, the composition containing the compound isadministered for at least 2 weeks, about 1 month to about 5 years, andfrom about 1 month to about 3 years.

V. Kits/Articles of Manufacture

The disclosure also provides kits for diagnosing, preventing, treatingor ameliorating the symptoms of a diseases or disorder in a mammal. Suchkits generally will comprise one or more of the pharmaceuticallyacceptable FVIIa modulator compositions as disclosed herein, andinstructions for using the kit. The disclosure also contemplates the useof one or more of the compositions, in the manufacture of medicamentsfor treating, abating, reducing, or ameliorating the symptoms of adisease, dysfunction, or disorder in a mammal, such as a human that has,is suspected of having, or at risk for developing a cancerous tumor or athromboembolic disorder.

Disclosed herein, in some embodiments, is a device for administering acomposition comprising a compound of Formula I:

wherein the device comprises a syringe.

In one embodiment the delivery system is a syringe. In anotherembodiment, the needle on the syringe is narrower than 20 gauge. Inanother embodiment, the needle gauge is from 20-33. In a furtherembodiment, the needle gauge is 28.

In yet another embodiment, the needle is a hypodermic needle used forinstant delivery of the compounds and compositions disclosed herein. Ina further embodiment, the hypodermic needle is a single use needle.

In yet another embodiment, the needle is a disposable needle.

In some embodiments, is a syringe used for delivery of the compounds andcompositions disclosed herein wherein the syringe has a press-fit (Luer)or twist-on (Luer-lock) fitting.

In one embodiment, the syringe is a hypodermic syringe. In yet anotherembodiment, the hypodermic syringe is a single use syringe.

In a further embodiment, the syringe is a single use syringe.

In another embodiment, the syringe is made of plastic or glass.

In a further embodiment, the glass syringe is capable of beingsterilized. In yet a further embodiment, the sterilization occursthrough an autoclave.

In another embodiment, the syringe comprises a cylindrical syringe bodywherein a compounds and/or composition disclosed herein is stored beforeuse. In other embodiments, the syringe comprises a cylindrical syringebody wherein a compounds and/or composition disclosed herein storedbefore use which allows for mixing with a suitable pharmaceuticallyacceptable buffer. In a further embodiment, the syringe contains astabilizer to stabilize a compound and/or composition disclosed herein.In some embodiments, the syringe comprises a cylindrical syringe bodywherein the body is compartmentalized in that each compartment is ableto store at least one component of a composition disclosed herein. In afurther embodiment, the syringe having a compartmentalized body allowsfor mixing of the components prior to injection at the tumor site.

In one embodiment is a delivery system wherein the system comprisesmultiple syringes. In another embodiment, each syringe of the multiplesyringes contains at least one component of a composition disclosedherein such that each component can be pre-mixed prior to injection orcan be mixed subsequent to injection at the tumor site. In a furtherembodiment, the syringes disclosed herein comprise at least onereservoir wherein the at least one reservoir comprises a compound ofFormula I, or a pharmaceutically acceptable buffer, or a combinationthereof.

Commercially available injection devices are employed, in their simplestform as ready-to-use plastic syringes with a syringe barrel, needleassembly with a needle, plunger with a plunger rod, and holding flange,which, as a rule, require skilled handling, especially if a subcutaneousinjection is to be performed, i.e., if the needle must first be insertedinto a position under the skin that is to be defined as precisely aspossible, and only then will the composition be injected. In a furtherembodiment, the delivery device is suitable for self-administration.

Numerous devices have been developed for injecting medication directlythrough the skin of a person without requiring a needle or otherapparatus for piercing or puncturing the skin. These needlelessinjection systems use a source of high pressure to force the liquidmedication directly through the skin. Various other devices are intendedto provide individualized needleless injections. In one embodiment, is adelivery system for delivery of a compound and/or composition disclosedherein without the requirement of a needle.

The present disclosure also provides therapeutic and diagnostic kitsthat typically comprise one or more of a compound and/or compositiondisclosed herein and instructions for using the kit in particularregimens or modalities. Likewise, the disclosure provides uses of thecompositions in a method for providing a biologically-effective amountof a therapeutic agent to a tumor site of a mammal in need thereof. Themethod generally involves at least the step of providing a compoundand/or composition disclosed herein to a mammal in need thereof in anamount and for a time effective to provide a biologically-effectiveamount of the therapeutic agent to particular cancerous cells, tissues,or organ(s) of the animal being treated. Modes of administration of thecompositions include, for example, systemic administration, or bydirect, indirect, or localized injection to a cell, tissue, or organ ofthe mammal using methodologies described herein.

In some embodiments, kits include a carrier, package, or container thatis compartmentalized to receive one or more containers such as vials,tubes, and the like, each of the container(s) including one of theseparate elements to be used in a method described herein. Suitablecontainers include, for example, bottles, vials, syringes, and testtubes. In other embodiments, the containers are formed from a variety ofmaterials such as glass or plastic.

The articles of manufacture provided herein contain packaging materials.Packaging materials for use in packaging pharmaceutical productspresented herein. See, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558 and5,033,252. Examples of pharmaceutical packaging materials include, butare not limited to, blister packs, bottles, tubes, inhalers, pumps,bags, vials, containers, syringes, bottles, and any packaging materialsuitable for a selected composition and intended mode of administrationand treatment. A wide array of compositions of the compounds andcompositions provided herein are contemplated as are a variety oftreatments for any disease, disorder, or condition that would benefit bymodulation of a coagulation cascade, a FVIIa, and/or a TF-FVIIa complex.

For example, the container(s) include one or more compounds describedherein, optionally in a composition or in combination with another agentas disclosed herein. In one embodiment, the container(s) optionally havea sterile access port (for example the container is an intravenoussolution bag or a vial having a stopper pierceable by a hypodermicinjection needle). Such kits optionally comprising a compound with anidentifying description or label or instructions relating to its use inthe methods described herein.

In some embodiments, a kit will typically includes one or moreadditional containers, each with one or more of various materials (suchas reagents, optionally in concentrated form, and/or devices) desirablefrom a commercial and user standpoint for use of a compound describedherein. Non-limiting examples of such materials include, but not limitedto, buffers, diluents, filters, needles, syringes; carrier, package,container, vial and/or tube labels listing contents and/or instructionsfor use, and package inserts with instructions for use. A set ofinstructions will also typically be included.

In a further embodiment, a label is on or associated with the container.In yet a further embodiment, a label is on a container when letters,numbers or other characters forming the label are attached, molded oretched into the container itself; a label is associated with a containerwhen it is present within a receptacle or carrier that also holds thecontainer, e.g., as a package insert. In other embodiments a label isused to indicate that the contents are to be used for a specifictherapeutic application. In yet another embodiment, a label alsoindicates directions for use of the contents, such as in the methodsdescribed herein.

In another embodiment, aqueous suspension compositions are packaged insingle-dose non-reclosable containers. In a further embodiment,multiple-dose reclosable containers are used, in which case it istypical to include a preservative in the composition.

In certain embodiments, the pharmaceutical compositions are presented ina pack or dispenser device which contains one or more unit dosage formscontaining a compound provided herein. In another embodiment, the packfor example contains metal or plastic foil, such as a blister pack. In afurther embodiment, the pack or dispenser device is accompanied byinstructions for administration. In yet a further embodiment, the packor dispenser is also accompanied with a notice associated with thecontainer in form prescribed by a governmental agency regulating themanufacture, use, or sale of pharmaceuticals, which notice is reflectiveof approval by the agency of the form of the drug for human orveterinary administration. In another embodiment, such notice, forexample, is the labeling approved by the U.S. Food and DrugAdministration for prescription drugs, or the approved product insert.In yet another embodiment, compositions containing a compound providedherein formulated in a compatible pharmaceutical carrier are alsoprepared, placed in an appropriate container, and labeled for treatmentof an indicated condition.

EXAMPLES

The various aspects and advantages of the present disclosure areillustrated by the following non-limiting examples:

Example 1 Lung Colonization by B16F10 Melanoma Cells in Mice

The compound of Formula I (3×50 mg/kg; 3×100 mg/kg) and a controlvehicle were administered subcutaneously 1.5 hours before tumor cellinoculation and then at 4.5 hours and 24 hours after tumor cellinoculation. Results showed that in the control vehicle experiment, asubstantial number of Bl6F10 colonies formed in the lung in the majorityof the inoculated mice. Results after administration of 3×50 mg/kgshowed substantially fewer colonies of Bl6F10 colonies formed in thelung compared to the control vehicle. Further, following administrationof 3×100 mg/kg also showed substantially fewer colonies of Bl6F10colonies formed in the lung compared to the control vehicle.

Example 2 Inhibition of Lewis Lung Carcinoma Tumor Growth in C57BL Mice

The compound of Formula I was administered in a gel formulationsubcutaneously starting 4 days after tumor cell implantation. Tumorvolume in the control experiment continued to increase from about 100mm³ at 6 days to above 400 mm³ after 13 days and above 500 mm³ after 15days after start of dosing. 100 mg/kg bid x4d followed by 60 mg/kg bidshowed a reduction in the tumor volume of Lewis lung carcinoma tumor inC57BL mice (P<0.01) compared to the control for the 6, 9, 13, and 15days after the start of dosing. Further, 150 mg/kg bid x4d, thenfollowed by a 90 mg/kg bid, also showed a reduction in the tumor volumeof Lewis lung carcinoma tumor in C57BL mice (P≦0.01) compared to thecontrol for the 6, 9, 13, and 15 days after the start of dosing.

Example 3 PK of the compound of Formula I Following SC Delivery of Depotand Gel Compositions to Rabbits

Shown below in Table 1 are pharmacokinetic data in rabbits for thecompound of Formula I following subcutaneous delivery of the FVIIamodulator for both depot and gel compositions to rabbits. Mean PlasmaConcentration curves for both the depot and gel compositions atdifferent concentrations and pH are shown in FIG. 6.

TABLE 1 Dose C_(max) Cmax/ T_(max) AUC_(0-∞) AUC_(0-∞)/ GroupFormulation (mg/kg) (μg/mL) Dose (hr) (μg · hr/mL) Dose 1  80 mg/mL Gel16 4.71 0.29 5.33 84.71 5.29 2  80 mg/mL Depot 16 9.38 0.59 3.33 98.246.14 3 120 mg/mL Gel 24 10.65 0.44 7.33 148.26 6.18 4 120 mg/mL Depot 2413.23 0.55 3.33 149.68 6.24 NA Baxter Nanoparticle 12 2.62 0.22 6 96.98.08

Example 4 Further Biological Analyses

A study was performed in cynomolgus monkeys with the compound of FormulaI to provide information on its pharmacokinetics following intravenousand subcutaneous administration and to determine its subcutaneousbioavailability. The test compound was administered intravenously in asolution (1.76 mg/mL) composition and subcutaneously in a gelcomposition (107 mg/mL). Following subcutaneous administration in a gelcomposition (107 mg/mL), The compound of Formula I exhibited a moderaterate of absorption and, on average, reached a maximum plasmaconcentration 3.33 hours after dosing (shown below in Table 1). Themaximum observed plasma concentration (C_(max)) following a 10.7 mg/kgsubcutaneous dose was 11.6 μg/mL, which was 74% of the C_(max) observedfollowing a 1.76 mg/kg intravenous dose. The terminal half-lifefollowing subcutaneous dose administration was 7.43 hours, which wassimilar to the gamma-phase half-life following intravenous dosing. Thesubcutaneous bioavailability of the test compound following a single10.7 mg/kg dose was estimated to be 138±33%. The relative standarddeviation for systemic exposure (AUC) following subcutaneous dosing was20.9% (n=3).

TABLE 2 Route of Administration PK Parameter Intravenous Solution^(a)Subcutaneous Gel^(b) C_(max,obs) (μg/mL) 15.7 (±1.8) 11.6 (±1.2) T_(max)(h) — 3.33 (±1.15) CL (mL/h/kg) 83.7 (±8.3) — CL/F (mL/h/kg) — 64.3(±15.0) Vss (L/kg) 0.430 (±0.044) — MRT (h) 5.15 (±0.42) — AUC ₀₋₄₈(μg·h/mL) 21.2 (±2.07) 171 (±35) AUC_(0-∞) (μg·h/mL) — 172 (±36)t_(1/2 α) (h) 0.162 (±0.030) — t_(1/2 β) (h) 2.19 (±0.13) — t_(1/2 γ)(h) 7.07 (±0.53) — Terminal t_(1/2) (h) — 7.43 (±0.18) Bioavailabilty(%) — 138 (±33) ^(a)Dosage = 1.76 mg/kg; n = 4. ^(b)Dosage = 10.7 mg/kg;n = 3.

Example 5 Plasma Concentrations of a Compound of Formula I andProthrombin Time Changes in C57BL/6 Mice

C57BL/6 mice were dosed with a compound of Formula I in a gelcomposition by subcutaneous injection twice daily for 2 days. Plasmaconcentrations of a compound of Formula I were measured by LC-MS/MS atselect time points following doses 3 and 4. Following drugadministration, plasma levels were elevated in a dose dependent mannerreaching 15 ug/ml 3 hours after dose 3 at 45 mg/kg/dose. Drug plasmaconcentrations at all dose levels had dropped significantly by 6 hoursafter dose 3 but were again elevated in a dose dependent mannerfollowing dose 4. Maximal drug plasma levels reached greater than 30ug/ml 2 hours following dose 4 at 45 mg/kg/dose and dropped to 13 ug/mlby 4 hours post dosing. Drug plasma concentration following dose 4 at22.5 mg/kg/dose rose to 11 ug/ml at 2 hours and stayed elevated at 4hours. Drug plasma concentrations for all dose levels were at or nearbaseline 18 hours following dose 4. Prothrombin (PT) times were measuredat 0 (predose), 2, 4, and 18 hours after the 4th dose administration. Asshown in FIG. 7, changes in PT times correlated well with changes indrug plasma concentrations with a maximal change in PT time of 1.8 timesbaseline noted at 2 hours following the 45 mg/kg/dose.

Example 6 Toxicology Studies of a Compound of Formula I

Cynomolgus monkeys were administered a gel formulation of a compound ofFormula I twice daily by subcutaneous injection for 28 or 29 consecutivedays at a total daily dosage of 0 (vehicle), 3, 12, or 36 mg/kg/day(HED=0.96, 3.84, and 11.5 mg/kg/day, respectively).

Clinical signs noted in the 36 mg/kg/day group males and femalesincluded low food consumption; pale body or facial area; and swelling,reddening and scabbing at the dose sites.

One female monkey assigned to the 36 mg/kg/day group had an abnormallyhigh activated partial thromboplastin time (aPTT) value prior to thestart of dosing and was euthanized after 3 days of dosing due to severeexternal hemorrhage.

Lower red blood cell counts, hemoglobin, hematocrit, and meancorpuscular hemoglobin concentration (MCHC) and/or higher reticulocytecounts and/or higher mean corpuscular volume (MCV) were observed in the12 and 36 mg/kg/day group males and females on study days 14 and 26.

The effects on red blood cell parameters at the 36 mg/kg/day dose levelwere more pronounced on study day 26 in comparison to study day 14.Compared to values for the control group, the mean red blood cell countat the 36 mg/kg/day dose level was decreased by 39% in males and by 31%in females on study day 14 and by 58% in males and 42% in females onstudy day 26. Mean red blood cell count at the 12 mg/kg/day dose levelwas decreased on study day 26 by 8% in males and by 17% in females, whencompared to values for the control group.

Histologically, injection sites with subcutaneous hemorrhage and edemaincreased in severity and incidence in a dose-dependent manner.

The sternum-bone marrow and spleen showed shifts indicative of increasederythropoiesis. The lack of clinical evidence for hemolysis and thebrisk erythropoiesis evident in the marrow and blood suggest that theRBC abnormalities observed are due to bleeding.

In males administered 36 mg/kg/day, minimal to mild widening of theinterstitium along the medullary rays was noted between distal straighttubules in the kidney medulla.

The NOAEL for subcutaneous administration of a compound of Formula I tomonkeys for 28 or 29 consecutive days was 3 mg/kg/day (HED=0.96mg/kg/day).

Example 7 Manufacture of a Solution Comprising a Compound of Formula I

Step 1. Clean, sterilize, and depyrogenated all equipment and materials,according to the manufacturer's standard procedures, that will come intocontact with the components of the composition or the drug product.

Step 2. Prepare the titration buffers.

-   -   a. Add 400 mL of sterile water for injection (SWFI) to a        sterile, depyrogenated 1 L glass beaker. Add 40 g of NaOH NF.        Add SWFI to a total volume of 500 mL. Add a stir bar and mix        until all NaOH is dissolved. Label.    -   b. Add 400 mL of SWFI to a sterile, depyrogenated 1 L glass        beaker. Add 18.23 g of HCl NF. Add SWFI to a total volume of 500        mL. Add a stir bar and mix until homogeneous. Label.

Step 3. Prepare the composition.

-   -   a. Add 2000 g of SWFI to a new sterile depyrogenated 4 L glass        beaker equipped with a sterile, epyrogenated magnetic stir bar.    -   b. Start stirring. Set the stirring speed so as to create a        slight vortex. Adjust as necessary throughout the process. The        solution temperature is controlled to between 20-25° C.    -   c. Add 38.4 g of NaOH NF and stir until dissolved.    -   d. Add 2.91 g of tromethamine USP and stir until dissolved.    -   e. Calculate the total amount of the compound of Formula I to        add to achieve a final concentration of 120 mg/mL. Correct for        water content and purity per manufacturer's C of A.    -   f. Add 50% of the calculated amount of the compound of        Formula I. Stir at a rate to keep all undissolved API well        suspended. An amber colored solution is obtained.    -   g. Insert a new, dedicated and calibrated pH probe into the        solution.    -   h. Add 20% of the calculated amount of the compound of        Formula I. Stir at a rate to keep all undissolved drug substance        well suspended.    -   i. If, after stirring for 30 minutes, a solution is not obtained        and the pH is below pH 10.0, raise the pH of the mixture by        adding 2 N NaOH to pH 11.0.    -   j. Add 10% of the calculated amount of the compound of        Formula I. Stir at a rate to keep all undissolved drug substance        well suspended.    -   k. If, after stirring for 30 minutes, a solution is not obtained        and the pH is below pH 9.0, raise the pH of the mixture by        adding 2 N NaOH to pH 10.0.    -   1. Add 5% of the calculated amount of the compound of Formula I.        Stir at a rate to keep all undissolved drug substance well        suspended.    -   m. If, after stirring for 30 minutes, a solution is not obtained        and the pH is below pH 8.9, raise the pH of the mixture by        adding 2 N NaOH close to but not over 8.9.    -   n. Add 5% of the calculated amount of the compound of Formula I.        Stir at a rate to keep all undissolved drug substance well        suspended.    -   o. If, after stirring for 30 minutes, a solution is not obtained        and the pH is below pH 8.9, raise the pH of the mixture by        adding 2 N NaOH close to but not over 8.9.    -   p. Add 5% of the calculated amount of the compound of Formula I.        Stir at a rate to keep all undissolved drug substance well        suspended.    -   q. If, after stirring for 30 minutes, a solution is not obtained        and the pH is below pH 8.9, raise the pH of the mixture by        adding 2 N NaOH close to but not over 8.9.    -   r. Add 5% of the calculated amount of a composition comprising a        compound of Formula I. Stir at a rate to keep all undissolved        drug substance well suspended.    -   s. If, after stirring for 30 minutes, a solution is not obtained        and the pH is below pH 8.9, raise the pH of the mixture by        adding 2 N NaOH close to but not over 8.9.

Step 4: Final adjustments to the composition

-   -   a. Adjust the pH to 8.6-8.9 with the 2 N NaOH or 1 M HCl.    -   b. Bring the solution to a final weight of 2568 g (2400 mL) with        SWFI.    -   c. Dispense 1.2 mL of drug product into each sterile        depyrogenated vial. Stopper each vial. Crimp seal each vial.        Inspect each capped vial for major defects such as cracked glass        or unevenly applied seals. Inspect each vial for particulate        matter. Affix an appropriate label to each vial. Store vials        refrigerated (5±3° C.)

Example 8 Animal Trials for Central Nervous System (CNS) Responses toCompounds of Formula I

To evaluate potential central nervous system (CNS) pharmacologicalresponses to a compound of Formula I, rats in 4 groups of 6 males eachreceived a single dose injection of a composition as described inExample 7. Doses were administered as subcutaneous injections at doselevels of 0 (vehicle), 30, 90, and 240 mg/kg.

Modified functional observational battery and qualitative motor activitydata were recorded for all animals 6 days prior to dose administration.Modified functional observational battery and qualitative motor activitydata were also recorded beginning approximately 30, 90, 150, 300, and1440 minutes following dose administration.

No treatment-related toxicity occurred at any dose level.

Example 9 Animal Trials for Respiratory System Responses to Compounds ofFormula I

To evaluate potential effects on the respiratory system of a compound ofFormula I, rats in 4 groups of 8 males each received a single doseinjection of a composition as described in Example 7. Doses wereadministered as subcutaneous injections at dose levels of 0 (vehicle),30, 90, and 240 mg/kg.

At the 240 mg/kg dose level, lower tidal volume was observed immediatelyfollowing dosing to 60 minutes post-dosing (up to 16% lower) and from226-300 minutes post-dosing (up to 15% lower).

Example 10 Animal Trials for Cardiovascular System Responses toCompounds of Formula I

To evaluate potential effects on the cardiovascular system of a compoundof Formula I, cynomolgus monkeys each received ascending singlesubcutaneous doses of a composition as described in Example 7. Doseswere: 0 (vehicle), 3, 12, and 36 mg/kg.

After administration of 36 mg/kg of a composition as described inExample 7, higher heart rate (up to 27% higher) and body temperature (upto 0.4° C. higher) were observed.

Example 11 Animal PK studies

In rats, dogs, monkeys, and baboons, the bioavailability of a compoundof Formula I administered subcutaneously in a solution ranged from 95%to 124%.

In dogs, the time to reach maximum plasma concentrations (T_(max))following subcutaneous injection of a compound of Formula I was 0.5hours.

In baboons, the time to reach maximum plasma concentrations (T_(max))following subcutaneous injection of a compound of Formula I was 2.75hours.

The terminal half-life (t_(1/2)) of a compound of Formula I followingsubcutaneous administration was 2.67 hours in the rat, 5.68 hours in thedog, 5.40 to 8.14 hours in the monkey, and 7.21 hours in the baboon.

Example 12 Phase I Clinical Trial Study Objectives

To determine a dose of a composition as described in Example 7 thatincreases prothrombin time by 2-fold (International Normalized Ratio ofProthrombin Time (INR)=2).

Investigational Drug, Dose, Route, Regimen

A composition as described in Example 7 was administered subcutaneouslyas a single dose regimen as follows: 0.20 mg/kg.

Results described in FIG. 11.

Example 13 Clinical Trial

Indication: Suppression of tumor growth, metastasis, and angiogenesis incancers in which progression of disease is dependent on factor VIIaproteolytic activity.

Study Objectives

Primary Objective: To determine a pharmacologically effective, single,subcutaneous dose of a composition as described in Example 7 in a cohortmean peak INR (International Normalized Ratio of prothrombin time[PT])≧2.0, or a peak INR≧3.0 for any subject.

Secondary Objectives: To evaluate the safety and tolerability of asingle, subcutaneous dose of a composition as described in Example 7,and to determine the pharmacodynamic and pharmacokinetic profiles inhealthy adults.

Study Design

Phase I, single-center, open-label, dose-escalation study of up to 5dose-level cohorts of a composition as described in Example 7administered subcutaneously as a single-dose regimen in healthy adults.

One to 4 healthy adults will be dosed in each sequential cohort after atleast 3 days of follow up between cohorts.

In the absence of dose-limiting toxicity (DLT), dose escalation willproceed to the next dose level until a pharmacologically effective doseis determined (cohort mean peak INR≧2.0 or a peak INR≧3.0 for anysubject) or the maximum planned dose of 3.0 mg/kg is achieved. If acohort mean peak INR of ≧1.7 but<2.0 (or an individual peak INR of ≧2.4but<3.0) is achieved without DLT then escalation to the next dose levelmay proceed but only at one-half the originally planned dose increment.DLT is defined as the development of any more-than-minimal adversereactions (ie, any Grade 2 or higher adverse event as defined by theNational Cancer Institute Common Terminology Criteria for AdverseEvents, version 3.0 [CTCAE]).

To assess the anticoagulation effect that corresponds with the plasmaconcentrations of a composition as described in Example 7, INRcalculated from the PT of each subject will be monitored at baseline, 8times on Day 1, and daily until the results are within the normal rangefor a minimum of two consecutive days. If a DLT occurs in 1 of 4subjects, dosing of additional subjects will proceed upon mutualagreement between the Medical Monitor and the Investigator followingreview of the event. An additional 1 to 4 subjects may be dosed at thatsame dose level. Dose escalation will proceed to the next dose levelonly if no more than 1 of 8 subjects experiences a DLT following thereview of safety data by the Medical Monitor and the Investigator. If 2or more subjects experience a DLT in a single dose level cohort, theprevious dose level will be established as the maximum tolerated dose(MTD). If no DLT occurs at any dose, the highest tested dose will be thefirst dose level of a composition as described in Example 7 that resultsin a cohort mean peak INR≧2.0 or a peak INR≧3.0 for any subject.

Because human toxicities are not yet defined for this drug and,therefore, attribution to the drug is problematic, all toxicities shouldbe considered as drug-related unless they are clearly not related (eg,environmental). Clinically meaningful toxicity defined by CTCAE andstudy drug relatedness of adverse events (AEs) will be determined by theprincipal investigator in consultation with the medical monitor of thestudy. Any subject who exhibits clinically significant bleeding duringthe study will undergo detailed investigations of the relevantcoagulation factors and platelet function after an appropriate studydrug wash-out period.

Study Duration

15±2 days per cohort

Study Population

Approximately 20 to 40 healthy adult men or women 18 to 65 years of age(4 to 8 subjects per dose-level cohort).

Study Endpoints:

Primary endpoint

-   -   a. Pharmacologically active dose (defined as the first dose        level that results in a cohort mean peak INR≧2.0 or a peak        INR≧3.0 for any subject), or MTD and associated DLT (CTCAE        Grade≧2 toxicity, regardless of causality)

Secondary Endpoints:

-   -   a. Adverse event profile    -   b. Plasma Cmax, Tmax, half-life, and AUC of a composition as        described in Example 7    -   c. Urinary excretion of a composition as described in Example 7

Investigational Drug, Dose, Route, Regimen

Factor VIIa modulator, a composition as described in Example 7,administered subcutaneously as a single dose regimen in five dose levelcohorts as follows: 0.05 mg/kg, 0.20 mg/kg, 0.80 mg/kg, 2.0 mg/kg, and3.0 mg/kg.

Visit Schedule

Screening visit and Study Days 1, 2, 3, and 15±2. Additional days may berequired based on laboratory values.

Assessments

Safety assessments will consist of adverse events, vital signs,electrocardiograms, laboratory assessments including serum chemistrypanel, hematology panel, coagulation panel, and urinalysis), andinjection site assessments.

Blood and urine will be collected for pharmacokinetic assessment.

Inclusion Criteria

-   -   To be eligible to participate in this study, a subject must meet        all of the following criteria:    -   a. Healthy woman or man 18 to 65 years of age, inclusive.    -   b. Body Mass Index 18.5-30.0 kg/m2 inclusive.    -   c. Normal baseline coagulation or deemed not clinically        significant by the investigator:    -   d. PT 11.5-14.5 seconds and aPTT 22-37 seconds.    -   e. Ability to understand the study, willingness to participate        in the study, and ability to provide written informed consent to        participate.    -   f. In good health (ie, no evidence of clinically significant        underlying medical condition). Stable, well-controlled        hypertension is allowed if not on medication.    -   g. Women must be amenorrheic for at least 12 months or have had        a total hysterectomy.    -   h. Available for follow-up assessments for 15±2 days.    -   i. Agree to not participate in contact sports or strenuous        activity during the 15±2 day study period.

Exclusion Criteria

A subject meeting any of the following criteria will be excluded fromthis study:

-   -   a. History of any clinically significant medical condition that,        in the opinion of the principal investigator, is defined as “not        in good health”.    -   b. Elective surgery, dental work, or regional anesthesia planned        during the trial period.    -   c. Known history of clinically significant bleeding after        surgery or childbirth (required blood transfusions) or after        dental extraction (required suturing).    -   d. Known history of clinically significant recurrent bleeding        episodes.    -   e. Known history of a congenital coagulation factor deficiency.    -   f. Known acquired or hereditary platelet disorder.    -   g. Known history of immunodeficiency.    -   h. Known vascular abnormality.    -   i. Any major trauma or surgery within 6 months, or biopsy        planned within the study duration.    -   j. Ongoing treatment with, or need for, oral antithrombotics        including anticoagulants (eg, coumadin) and antiplatelet agents        (eg, aspirin).    -   k. Sexually active men unwilling to use adequate contraceptive        protection or unwilling to refrain from sperm donation for        entire duration of the study.    -   l. Presence of any acute symptoms of headache, rhinitis, cough,        sore throat, fever, nausea, and/or vomiting within 3 days of        Study Entry.    -   m. Use of aspirin or other nonsteroidal anti-inflammatory agents        (NSAIDs) within 14 days of Study Entry, or planned use within        the study duration.    -   n. Use of alcohol, tobacco, or other drugs (prescription or        over-the-counter) within 3 days of Study Entry, or planned use        within the study duration.    -   o. Uncontrolled hypertension (systolic>160 or diastolic>100).    -   p. Positive stool occult blood test.    -   q. Chronic active hepatitis B or C, as confirmed by laboratory        testing at Screening.    -   r. HIV infection, as confirmed by laboratory testing at        Screening.    -   s. Renal insufficiency (BUN or creatinine>upper limit of normal        [ULN]).    -   t. Hepatic disease (AST, ALT, alkaline phosphatase, total        bilirubin, or GGT>ULN).    -   u. Contraindication to systemic anticoagulation.    -   v. Anemia (Hgb<12 gm/dL).    -   w. Thrombocytopenia (platelet count<150,000/μL).    -   x. Hematuria (microscopic).    -   y. Participation in any study of an investigational device,        medication, biologic, or other agent within 30 days prior to        enrollment, or planned participation within the study duration.    -   z. Participation in a prior cohort of this study.

The examples and embodiments described herein are for illustrativepurposes only and various modifications or changes are to be includedwithin the spirit and purview of this application and scope of theappended claims.

1.-176. (canceled)
 177. A composition comprising: a) a compound ofFormula I or a salt thereof:

and b) a thrombin modulator.
 178. A composition comprising: a compoundof Formula I or a salt thereof:

wherein the composition is stable with respect to compound degradationfor at least about 1 month.
 179. A composition comprising: a) a compoundof Formula I or a salt thereof:

and b) an amino acid buffer.
 180. A combined dosage comprising: a) acompound of Formula I or a salt thereof:

and b) an additional therapeutic agent.
 181. A composition comprising: acompound of Formula I or a salt thereof:

wherein the pH of the composition is between 7 and
 9. 182. A compositioncomprising: a) a compound of Formula I or a salt thereof:

and b) a divalent cation.
 183. A composition comprising: a compound ofFormula I or a salt thereof:

wherein the composition is formulated for administration by IV bolus orIV infusion.
 184. A composition comprising: a compound of Formula I or asalt thereof:

wherein the osmolality of the composition is from about 280 mOsm/kg toabout 320 mOsm/kg.
 185. A kit comprising, a) a container comprising: i.a compound of Formula I or a salt thereof:

and ii. an additional therapeutic agent; and iii. a buffer and/ordiluent; and b) a set of instructions.
 186. A composition comprising: acompound of Formula I or a salt thereof:

wherein the composition is isotonic.